!!Season 1
* Leonard's DespairEventHorizon in "The Nerdvanna Annihilation" over Penny's anger-induced jabs at the four's lifestyle.
* Leonard's story where he thought he was going to his first birthday party only to realize his grandfather passed away.

!!Season 2
* Leonard's HilariouslyAbusiveChildhood is, like Amy's past, funny but sad. For instance, ''he never had a birthday party as a kid'', and he essentially had to give up his childhood to become the genius he is now. Poor guy.
** "The Maternal Capacitance" is one long episode designed to make you cry for Leonard. Poor guy with a mother like that, for so long... [[https://www.youtube.com/watch?v=7zJiPKhD9OA he actually built a hugging machine because there was such a lack of affection in his house]]. If that's not bad enough, his father used to borrow it... (To some, this CrossesTheLineTwice.)
** [[https://www.youtube.com/watch?v=LTI0eF-WuMA His mother's effect on Penny]] is quite a tearjerker in its own right.
* [[https://www.youtube.com/watch?v=o0h0qZCjR_k In "The Friendship Algorithm", Sheldon is at a bookstore looking for a book about making friends when he strikes up a conversation with a little girl.]] They get along, with Sheldon offering to take her to a zoo before Leonard drags him away because of [[MistakenForPedophile how bad it looks]]. It's set up as a [[SugarWiki/FunnyMoments gag]] and it works as one, but it also fits here because we (the audience) know that, for all his quirks and annoying habits, Sheldon would never do something like that to her and she would probably be relatively safe with him. Child abduction and abuse are horrible, it's just people have to assume the worst even from someone who wouldn't even have a sexual encounter with a willing woman his age (Amy, Season 5). The absolute worst part: Sheldon was trying to learn how to make friends and that girl probably would've become a close friend (It's Sheldon, would it have been weirder than half the stuff he does?)
** Really, it was sad not because of the specific events but because it once again showcased that on an emotional level Sheldon isn't much older than that girl, which has been the source of most of the problems in his life.
* In the season finale, [[https://www.youtube.com/watch?v=toMtj5Q9cYQ when Penny quietly admits to herself that she wishes Leonard wasn't going away]] for the whole summer to the North Pole.

!!Season 3
* [[https://www.youtube.com/watch?v=bjNh8UYO_o8 Sheldon's meltdown]] in "The Guitarist Amplification."
* While it's still PlayedForLaughs, hearing Leonard's voice waver before he breaks down while talking about his mother in "The Pants Alternative" definitely counts.
* Leonard and Penny breaking up. Leonard's heartbreak was devastating to watch, then what we heard about how hard he was taking it from Sheldon.
** And for my money, there was Penny's agonized sobbing as she broke up with Leonard. My interpretation is that she really did love him, but was afraid she couldn't be what he needed.
* In "The Precious Fragmentation", [[http://youtu.be/nxLi5wnmGpA?t=1m40s Howard's little breakdown upon discovering an Alf Doll]], bringing back memories of his father's abandonment.
--> '''Howard''': When I was eleven my mother got me one to help me sleep after my dad left. I used to pretend my dad had moved to the planet Melmac and Alf was going to bring him back... but he never did. *''Tearfully''* Where's my daddy, puppet? Where is he?

!!Season 4
* Sheldon's ''Franchise/StarTrek''-based fanscript in "The Thespian Complex," with [[https://www.youtube.com/watch?v=ba7XwD550kI him leaving his mother to go to the future and Penny insisted on reversing the roles (She would play Spock and Sheldon would play his mother). Sheldon's script was based on the idea that nobody appreciated him or his intelligence, but portraying his mother made him realize how much his mother loved him]]. Of course, this isn't stated out loud but in Sheldon having an emotional breakdown [[OffTheRails playing both his mother and his ten year old self]].
* Whenever Amy's childhood is revealed, it's [[PlayedForLaughs funny]] but usually kinda sad. For instance, she never had friends as a kid:
-->'''Penny:''' Wait, you've ''never'' been to a ''sleepover''?
-->'''Amy:''' No, unless you count the time I had influenza and shared a hospital room with a little Vietnamese girl... She didn't make it through the night, but up till then it was kinda fun.
** In [=S5E2=], when she pleads to Penny, [[https://www.youtube.com/watch?v=W7JvTtpOjU0 "No, I'm sorry, ''please'' don't cut me out of your life!"]]
** In Season 5, she revealed that her cousin was paid off to go with her to junior prom, and he instead spent the money on drugs...
-->'''Penny:''' ''(choked up)'' Give her the corsage, Leonard.
* Leonard started dating Priya in what looked like a very long term and serious relationship, so while Penny put on a brave face you could tell it was eating away at her that Leonard had moved on (with someone who was more compatible with him on paper as well) and she eventually broke down in tears. [[https://www.youtube.com/watch?v=sKMOFfrY7ME It probably didn't help that Amy was anticipating this all along the way and told her repeatedly that it was going to happen eventually, but the emotions that go on in such a scenario are hard to deal with]].
* In "The Justice League Recombination", they go to the comic book store for the New Year's Eve party. When midnight strikes, [[https://www.youtube.com/watch?v=-v7N9_MpWPo Zack kisses Penny with her looking guiltily and oh so sadly at Leonard. Leonard looks extremely sad as well, as if he]] was holding back tears. The Auld Land Syne theme doesn't help at all, it only makes the whole situation sadder.

!!Season 5
* [[Series/StarTrekTheNextGeneration Brent Spiner]] [[spoiler: tearing open Sheldon's mint condition Wesley Crusher action figure autographed by Wil Wheaton, which had finally ended their rivalry,]] is [[https://www.youtube.com/watch?v=PiX4T0bIDBo kind of cruel when you think about it]].
* Amy's isolation in "The Isolation Permutation" rings true, especially since her interactions with Penny made her ecstatic to be friends with a cheerleader type and to be excluded at all brings back ALL those painful memories.
** Her comparing herself to a [[ItMakesSenseInContext brain tumor]] is [[https://www.youtube.com/watch?v=Rng-AuoPtVE ''painfully'' unfunny]].
* In "The Ornithophobia Diffusion", Sheldon has a fear of birds and a blue jay lands on the apartment windowsill. The blue jay flies in and Sheldon, with the help of Bernadette and Amy, manages to overcome his fear. [[https://www.youtube.com/watch?v=wXXi80gLAmw In the midst of just falling in love with the bird (calling it Lovey Dovey despite not being a dove) he opens the window and the blue jay flies out]].
* In the Stephen Hawking episode, Sheldon has to do tasks for Howard, who is helping him with his wheelchair. When Bernadette gets Sheldon to go dress shopping with Howard's mother. [[InnocentlyInsensitive When Sheldon points out that her weight makes it hard for her to find a good dress]] she breaks down [[IWasQuiteALooker saying that she was quite a looker]] until she ate all the candy she received as gifts from her dates, [[{{Irony}} leading to the start of her weight issues]] and makes him hold her. For a loud, annoying JewishMother, [[https://www.youtube.com/watch?v=F4W_whhktoQ that really was depressing]].
* Howard going to see Bernadette after she finds out that [[https://www.youtube.com/watch?v=LbcYGQtNHOQ he previously hired prostitutes, had sex]] with his cousin[[note]]'''second''' cousin![[/note]] and had a threesome with Raj and a women dressed as Franchise/SailorMoon. The show comes ''this'' close to making you think they are about to break up.
-->'''Howard:''' [[https://www.youtube.com/watch?v=4ig3VRlRoqY Tell her I'm really sorry. And if she doesn't want to marry me, I get it. But what I really want her to know is the guy that she is really disgusted by is the guy that I'm disgusted by, too. But, that guy doesn't exist anymore; he's gone. And the reason is because of her. So, if this relationship is over, let her know that she made me a better man, and tell her thank you.]]
** Also a [[SugarWiki/HeartwarmingMoments Heartwarming Moment]], especially considering what happens afterwards.
** Bernadette also has a small breakdown when she learned Penny knew all about his past and kept silent because she didn't expect them to go past "meeting his mom" or "sex." That must have been really difficult for her, feeling like the whole world was lying to you.

!!Season 6
* [[https://www.youtube.com/watch?v=b2ADLgwCr1I Every]]one's WhatTheHellHero to Penny after discovering that she has ''never'' told Leonard that she loves him. She admits that she does to Amy and Bernadette, but hasn't told Leonard simply because she thinks he'd make a big deal out of it.
** Becomes sadder when you realize that Leonard grew up with an emotionally distant mother who never said it either. Is it any ''wonder'' why the poor guy simply wants to be told it every now and again?
** Even worse - another interpretation of that scene is that she ''doesn't'' love him. She seems like she's only really saying it because otherwise she'd look like she was just using him for sex.
* Howard's "triumphant" return home from space... [[https://www.youtube.com/watch?v=7tGLOUelgiE only Bernadette's sick]], [[https://www.youtube.com/watch?v=UikkixGOWH8 his mother is hooking up with their dentist]], [[https://www.youtube.com/watch?v=zxHGA0OB7uY Raj is doing friend stuff with Stuart that he used to do with Howard]], and [[https://www.youtube.com/watch?v=eShTffB8ApI Sheldon/Leonard/Amy/Penny are occupied with game night]]. He's left to spend the evening by himself in a local diner (where the waitress offers him some cheesecake on the house but doesn't stick around for chit-chat)... [[https://www.youtube.com/watch?v=ZjyLNmnLBBo he's left sadly singing "Rocketman" to himself as the episode ends. To top it off, he caught Bernadette's cold]].
* A jerk he sometimes might be, but you can't help feeling sorry for Raj in [[https://www.youtube.com/watch?v=kNYJt1zft9o this situation]]. It seems funny to outsiders, but selective mutism is real and an awful, awful condition to suffer from.
* Howard's story to Bernadette about how he used to put on a magic show for his mother, and that it would help her forget how lonely she was.
* There's just something so heartbreaking (even if it was part of a genuine heartwarming moment right before) in the scene where Leonard goes back to his apartment to let the news that [[spoiler: Penny loves him]] sink in. It makes it seem like he genuinely didn't believe she did before. You really just want to hug the guy.
* Was a little depressing to hear ALL of the guys admit that they didn't do much "father/son" stuff with their dads when they were younger...
* [[https://www.youtube.com/watch?v=K6-GRWmk4Ss Sheldon's story about how his "Pop Pop", the only person that ever actually encouraged him to pursue science, died when he was little and the only thing he wanted from Santa for Christmas the following year was his Pop Pop back]]. No wonder he's such a Scrooge.
** More than that, his other reason for wanting his Pop Pop back was because he didn't want his Mee-maw to be sad anymore. We very rarely see Sheldon show that level of awareness and empathy towards someone else, making it clear how much he adores his grandmother.
* [[https://www.youtube.com/watch?v=VMiA5po2Keo Amy and Raj bonding over how lonely their lives have been]]. You just want to hug them both.
* "The Bakersfield Expedition" was a spirit-breaking ordeal for all four guys as Leonard's car was stolen, Sheldon was hit with a Slurpee thrown from a passing car, and they were subject to ridicule at the diner where they finally got to call for help. Even SHELDON was left depressed by the whole thing. The fact that the girls got hooked on comic books while they were gone was a small bright spot in an otherwise depressing episode.
* Lucy running out on her and Raj's date in "The Monster Isolation" and Raj's resulting HeroicBSOD leading to him deciding to completely shut himself off from the rest of humanity. Later when she comes to apologize we find out that she has many of the same issues and anxieties that he does and ran away because she was scared.
* Raj's complete and total heartbreak when [[spoiler: Lucy breaks up with him via text message.]]
* The letter from Howard's dad in "The Closet Reconfiguration", which does nothing but give Howard a HeroicBSOD upon remembering he still had it, and sealed. Even when the rest of the crew come up with a ploy to tell him a plausible message that the letter could've held (since he doesn't want to know what the letter said), he's still holding back tears as each person goes through their scenario.
* The introduction of Arthur Jeffrey's AKA Professor Proton, the childhood idol of Sheldon who once hosted a science-themed kids show in Texas. While Sheldon still idolizes the man, it's clear to everyone else just what a toll life has taken on the old man, as hosting the show cost him any sort of serious career in science. By the time he first appears on the show, he is ancient and spent, and understandably somewhat bitter that all anyone will remember about him is Professor Proton.

!!Season 7
* YMMV, but anyone else feel for Raj during Howard's song to Bernadette when Howard calls her his best friend? I mean, Raj is coming off a breakup with Lucy, is watching Howard celebrate all the things Raj doesn't have, and on top of that, hears Howard admit that he's been replaced as his best friend. Kind of Fridge Sadness in a way.
* Penny sees Lucy at the restaurant and bugs her to see Raj in person after she dumped him via text/e-mail. Raj is happy to see her again, but she tells him that she's seeing someone else. Now it seems like Raj has SEVERE trust issues... Penny sets him up with another girl and, without any provocation at all, IMMEDIATELY suspects she's already got a boyfriend and accuses her of lying about it when she says she doesn't. This guy needs a break SOON.
* Although it was played for the gag, [[http://youtu.be/b2I8JHewYS0?t=2m45s the scene where Amy imagines her life if she never met Sheldon]], showing her sitting completely alone in her apartment, celebrating her own birthday with a tiny cupcake. Then her breaking into tears while halfway through singing herself happy birthday, is really quite heart breaking. It definitely hammers in the fact that before she met him, she had no one whatsoever who cared about her.
** It's more heartbreaking when you realize this is a very sad case of Truth in Television. A lot of people like Amy probably DID spend birthdays all alone unwillingly and Amy was fortunate enough to find people to free her from her loneliness. This troper spent a few alone and the heartache that Amy feels is very real. Spending your own birthday all alone, with only a tiny cupcake and no one to even wish you happy birthday, leaving you in tears... How this could even be CONSIDERED a gag is beyond this troper.
* [[http://youtu.be/80i58nEykos Stuart imagining that he's cool and dating Penny]] starts off quite funny, until the scene cuts back to reality showing him sitting alone in a near empty restaurant, the look on his face when he zooms back and realises how alone he is, is really quite sad.
* "The Proton Transmogrification" is all about the death of [[spoiler:Arthur Jeffries, A.K.A, Professor Proton]]. Sheldon at first appears to take the news quite well, but then he has a breakdown and locks himself in his room. He dreams that [[spoiler:Arthur]] visits him, and there Sheldon explains that since his father and grandfather died when he was young, with [[spoiler:Professor Proton]] dead, all the men he looked up to were now gone. [[spoiler:Arthur]] gives Sheldon one last piece of advice: to appreciate his friends. When Sheldon wakes up and sees Leonard, the first thing he does is give him a heartfelt hug, an unusually emotional move from the typically detached Sheldon.
** Also Professor Proton's first episode, when Sheldon admits that as a child, he didn't have any friends. He sounds SO vulnerable when he explains how Professor Proton would do science with Sheldon every afternoon.
* Just when you think life couldn't treat Stuart any worse, his comic shop burnt down.
** Stuart being the woobie is just not funny anymore. Tropers who are battling depression themselves just want to give that poor guy a hug and tell him that everything is gonna be alright.
* Sheldon's mental breakdown that life is changing and it needs to stop. He takes a trip on a train to let him straighten his ideas.
** Amy had an emotional breakdown at the end of the episode once it finally sunk in that Sheldon was gone.

!!Season 8
* Raj confronting Sheldon after the latter abandoned him in a steam tunnel due to panicking over oversized rats. The anger and bitterness is saddening as he accuses Sheldon of betraying him after he tried to help him out, calling him a personal and moral coward. [[https://www.youtube.com/watch?v=I1p6pggFiDo And all Sheldon does is call back to a previous statement about how much Raj annoys him for stating the obvious]].
* In "The Space Probe Disintegration", Leonard and Sheldon talk about how they make compromises for each other, leading to Leonard telling Sheldon that the only reason he doesn't live with Penny is because of Sheldon (who had an emotional breakdown the last time the subject was brought up). Sheldon apologizes and tells Leonard he's all right with Leonard going to live with Penny, and starts crying because he's "imagining a world without my best friend in it". Leonard says he's only going to be living across the hall from him:
--> '''Sheldon:''' Either way, I just wanted to say I'm aware of how difficult I can be, so I just wanna say... thank you for putting up with me.
** Leonard's voice cracking when he replies with "''Buddy...''" only makes things worse.
* Howard's mother passing away and Sheldon's genuine consolation.
** The serious tone Howard's voice takes when he says "my mom died."
** The final moment of that episode qualifies, too -- while Howard and Bernadette travel to Florida (as Mrs. Wolowitz died there), the rest of the friend circle gathers in Sheldon and Leonard's apartment and reminisces about her, ending with Leonard leading a toast to "Mrs. Wolowitz, a loving mother... to all of us."
** What makes it even worse is that due to Howard's feud with Stuart after the latter began living in the Wolowitz house and being spoiled by Debbie, it's heavily implied that he had stopped visiting frequently.
** The whole thing gets ramped UpToEleven when you remember that this is a case of RealLifeWritesThePlot -- the actress who provided the voice of [[TheUnseen Mrs. Wolowitz]] passed away for real, and so the entire plotline was added to the show. To at least some extent, the grieving shown by all the actors is genuine.
* "The Intimacy Acceleration" has several, but the worst is Howard tearfully recalling that he was too busy to drive his mother to the airport to catch her flight to Florida; he made her take a taxi instead. He lost the opportunity to spend more time with her, and truly NeverGotToSayGoodbye.
** A subplot of the episode involves the airline losing the bag containing Mrs. Wolowitz's ashes. But the airport worker trying to help Howard and Bernadette ''isn't'' a {{Jerkass}}: she doesn't really know what to do with the situation (which is already incredibly stressful), and she's being forced to deal with two understandably upset but ''extremely'' angry people, one of whom threatens to kill her if the ashes aren't returned right away.
** The title of the episode refers to Penny and Sheldon taking a test that can apparently make people fall in love within minutes. One part of the test is revealing secrets to each other. Penny confesses that deep down, she wishes that she was as smart as the rest of the group, hinting that she might be insecure about her own intelligence. Sheldon, meanwhile, notes he wishes he could "read minds"--that is, understand human interaction and emotion as well as Penny and others do. There is a kind of [[FridgeLogic Fridge Sadness]] here; Sheldon is so emotionally stunted that he considers socializing with others and having basic empathy a superpower. It also reveals that he genuinely can't differentiate between people being annoyed at him or other things; again, Fridge Sadness suggests that he's so used to people finding him bothersome that he ''expects it to happen'' whenever he meets someone new.
* In "The Leftover Thermalization", a blackout at Howard's mother's house means that all the food in the freezer is thawing, and there's no alternative but to cook it all. Howard gets emotional about having to cook the last meal his mother ever made, noting that she believed her cooking could cure anything. He invites all his friends over, saying that it's like her mother is feeding them one last time.
** The moment when it seems to finally dawn on Howard that he really isn't ever going to see his mother again. The man can only get teared up in his wife's arms.
* In "The Commitment Determination", Sheldon offends Amy for the umpteenth time. Sheldon doesn't understand what he did wrong, but Amy is really upset because he was thinking more about ''The Flash'' series more than her during their fifth anniversary of their first date. Eventually, after stumbling through the episode with his DumbassHasAPoint behavior when it comes to relationships, he Skypes Amy. [[spoiler: Amy, sick of Sheldon's inability to read people and general selfishness, tells him she wants to step back in their relationship and ends the call. Sheldon, confused, turns to his Gollum figure and asks the ring expert what to do with the engagement ring he has.]] Unlike other serious moments in the show that may be spoiled by MoodWhiplash, there is no laughter after this turn of events. It just cuts to the credits.
** [[https://www.youtube.com/watch?v=LuJ4Prn9b6Y Leonard and Penny are on their way to Las Vegas to get married]], both are excited and then Leonard reveals that there was an incident overseas when he drunkenly made out with a drunk lady. Penny is shown to be disappointed by the news and more peeved about the timing he chose to drop such news on her. Also, she was always faithful to him.

!!Season 9
* The season premiere was somber to say the least. Leonard and Penny are finally married, but their relationship may never be the same with all the tension related to Leonard's Season 8 finale admission (AND the fact that she's a co-worker). On top of that, Sheldon and Amy seem to be officially broken up and Sheldon is having trouble dealing with it...
* After Leonard moved in with Penny, Sheldon is worried that he is going to see less and less of Leonard and lists all the reasons why they would have dinner with each other on special occasions. The first two reasons are funny only for it to end with him claiming Amy will marry someone else, someone better than Sheldon. It seems the idea he may have permanently lost Amy has finally sunk in, and it's hit so hard he'll actually resort to self criticism. Sheldon has such a sad look on his face that he really sells it.
* After Sheldon convinces himself to go to propose to Amy, he walks to her apartment and sees her returning from a date and receiving a kiss. He doesn't say a word, just puts the ring back in his pocket and walks away. It's a credit to Jim Parsons' acting ability that you can tell how utterly crushed Sheldon is without speaking.
** The depth of Sheldon's feelings really hits Leonard and Penny hard after they find out about his plan to propose. When Sheldon snaps at Penny "I SAID I'M FINE", it looks like she's trying not to cry.
* In ''The Mystery Date Observation'', Amy finds out she is dating a Sheldon Cooper fanboy. While the laugh track is quite amused, the fact that all the things he keeps raving about were things that involved Sheldon being a selfish ManChild towards her gets kind of depressing.
* In ''The Platonic Permutation'' so they don't waste the tickets, Sheldon and Amy decide to go to the Aquarium café Thanksgiving Dinner as friends. Though the food proves to be awful, the two have a fun time together. So much so, that Amy begins to remember why she wanted to date Sheldon in the first place and begins to miss their interactions. That night, she calls him and asks if they can get back together. Sheldon, still having problems with their break up and getting over her, turns her down stating they need to stay friends for the moment. Amy quietly accepts this, while looking heartbroken. Worse still, it's the end of the episode, so we're just left with a look at Amy's disappointed face.

!!Season 10
* While ''The Birthday Synchronicity'' is otherwise a very heartwarming episode with Howard and Bernadette's daughter being born, Howard briefly laments that Mrs. Wolowitz would have made an amazing grandma if she was still alive.
* In "The Emotion Detection Automation," Sheldon is shown to be deeply upset by the fact that he has such a hard time reading other people's emotions, and that he genuinely dislikes his (apparent) LackOfEmpathy. However, as Amy points out, the mere fact that he's upset by this shows how far he's come since earlier seasons.
* After nine seasons, we finally learn why Sheldon always knocks three times before he enters a room: [[spoiler: when he was a kid, he accidentally walked in on his father having an affair.]]

!!Season 11
* Sheldon and Georgie's animosity and reconciliation. It turns out that Georgie had to grow up far too fast after their father died to take care of the rest of the family while Sheldon was studying abroad, and he kept the fact that they (especially their mother) were suffering from Sheldon to protect him.
* A deleted scene has Sheldon and Amy receive a wedding present from a deceased Stephen Hawking. Leonard is on the verge of tears when he comments that Hawking must've sent it shortly before he died. Given what an iconic and revolutionary figure Hawking is in science, we can only imagine how hard the guys must've taken the news of his passing.
* In her vows, Amy admits that while she dreamed of her wedding day as a child, she eventually stopped... because she thought that day would ''never come''. [[EarnYourHappyEnding Thank God times have changed.]]