!!Season One
* Leonard's DespairEventHorizon in "The Nerdvanna Annihilation" over Penny's anger-induced jabs of the four's lifestyle.

!!Season Two
* 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... he actually built a hugging machine because there was such a lack of affection in his house.
*** His father used to borrow it... (To some, this CrossesTheLineTwice.)
*** His mother's effect on Penny is quite a tearjearker in its own right.
* 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 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, for all his quirks and annoying habits, would never do something like that to her and she was probably 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 worse part: Sheldon was trying to learn how to make friends and that girl probably would've been 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, when Penny quietly admits to herself that she wishes Leonard wasn't going away for the whole summer to the North Pole.

!!Season Three
* 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 devestating to watch, that what we heard about how hard he was taking it from Sheldon.
* In "The Precious Fragmentation", 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 Four
* Sheldon's ''Franchise/StarTrek''-based fanscript in "The Thespian Complex," with 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, "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. 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, 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 Five
* [[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 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 estactic 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 ''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. 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, that really was depressing.
* Howard going to see Bernadette after she finds out that 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:''' 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 Six

* Everyone'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 realise 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... only Bernadette's sick, his mother is hooking up with their dentist, Raj is doing friend stuff with Stuart that he used to do with Howard, and 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)... 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 [[http://www.youtube.com/watch?v=ab_qHHaAEUs&feature=relmfu this situation]]. It seems funny to outsiders, but selective mutism is real 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 geniune 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...
* 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.
* 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.

!!Season Seven
* 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. Kinds 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 provokation 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, the scene where Amy images 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 defiantly hammers in the fact that before she met him, she had no one what so ever who cared about her.
* 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.
* Just when you think life couldn't treat Stuart any worse, his comic shop burnt down.
** Followed by Sheldon's mental breakdown that life is changing and it needs to stop. Sheldon takes a trip on a train to let him straight his ideas.
*** Amy had an emotional breakdown at the end of the episode once it finally sunk in that Sheldon was gone.