This is based on opinion. Please don't list it on a work's trope example list.
Tearjerker / Foster's Home for Imaginary Friends
In general: Mac's mom is always at work, we never see his dad, he's constantly tortured daily by his older brother, it's implied that he doesn't have any friends at school and is a common target for bullies, his imaginary friend is a huge jerk to him yet he's so sweet that he still visits him every day.
Bloo and Mac having to split up in the pilot episode, especially after Mr. Herriman shamelessly breaks his spirit by tell Bloo to his fact that Mac is never coming back. He's seen it a million times.
Mac coming home from his first visit to Foster's after dropping off Bloo, with a handful of Coco's eggs. He just walks in and glumly walks back to his room while Terrance follows and repeatedly smacks him in the back of his head.
Terrance: Where were you, anyway, stupid? What are those stupid eggs, stupid?? Where's that stupid little blue friend of yours, stupid''? Mom told ya to get rid of him!! Ho-ho-hoo boy! If you didn't, you're gonna be so-
Mac: (finally turning around and screaming): I WAS NOWHERE AND THEY'RE NOTHING AND I TOOK CARE OF IT!! HAPPY?!
(Terrance looks at him, speechless, as Mac slams his bedroom door behind him).
When you think about it, it's rather sad that all of these regular characters are imaginary friends ready to be adopted, but who no child wants, apparently.
The series finale. Looks like Mac's moving away! Well he did move. Just to the apartment next to his because his mom needed a larger working space.
Good Wilt hunting reveals Wilt's past. Wilt ran away from his kid when they lost a basketball game, and thought that he could never forgive him. Turns out, this hurt him more than anything, and the flashback scene at their reunion is heart-wrenching.
You can't help but feel sorry for Frankie missing the concert in "Imposter's Home for... Um Make 'em up Pals".
The episode that first introduced Goo. She spends most of the episode being loud, talkative, clumsy, and obnoxious, incessantly accidentally creating countless imaginary friends which became residents of the house, leading to the house getting overcrowded. Mac tries to get her to stop, but she is oblivious to the fact that she is causing problems. And as everyone believes it's Mac who keeps letting her into Fosters and has a crush on her (in both cases, it's really Bloo) when the house eventually becomes so crowded they main cast has to sleep on bus, Frankie and Mr. Herriman sympathetically but firmly tell Mac that he is no longer allowed at Fosters because he "can't stop bringing Goo there". Then everyone gives Mac a sad look (except Bloo who gives an apologetic look, since he was really responsible.) Mac then releases a shocking "The Reason You Suck" Speech... which leads to Goo's eyes welling up with tears, and the girl just leaves. Mac later finds Goo in a room crying, and she tearfully admits that the reason she creates so many imaginary friends is because she has no real friends. She then verbally abuses herself for being such an annoying screw-up. This leads to a Crowning Moment of Heartwarming when Mac takes back everything he said, apologizes, and comforts the poor girl, telling her that he likes her and appreciates her imagination and niceness. Goo then responds by giving Mac a big hug.
The speech from Mac itself is acidic enough:
Mac: I don't like you! (Beat) Don't you get it? Nobody likes you! You're annoying and weird and you talk too much and Bloo's name is not Chester, Mr. Herriman is not a badger, that's not how you play checkers, and protein doesn't come from bananas, it comes from nuts, which you don't need to eat more of because you are nuts! You're chock full of nuts! You're so nuts, you drive ME nuts! (Jumps in Goo's face) Get it? Get it? Get it? Get it? Get it? Get it? Get it?! Everybody thinks you're a nuisance and they all want you to just GO HOME!!!
The Bookends finale shot. After years of seeing the house be drawn as part of the opening title sequence, the cast of the show finally say goodbye by un-drawing the house in the final shot.
In "The Sweet Stench of Success", there's a scene where Mac and Bloo are sad about being away from each other, and a montage plays over their sadness.
In "Who Let The Dogs In", when Eduardo says goodbye to the puppies and one of them snuggles into his arm before Frankie takes him away. The look on his face afterwards is heartbreaking.
In "Affair Weather Friends", a sugar-crazed Mac's acting out of an imagined conversation between him and Bloo where he imagines Bloo insulting him, saying he doesn't need Mac, and leaving for good. It shows that his biggest fear is losing his best friend.
Mr. Herriman's verbal beatdown of World in "Destination Imagination". It's the scolding every kid dreads, and World looks like he's having a freakin' panic attack!
Frankie's backstory according to the Tweets made by Craig McCracken. Because Frankie's dad (who was also Foster's son) was disillusioned over Imaginary Friends thanks to his experiences with Mr. Herriman, Frankie was never allowed to have or create one, and she was forced to get rid of the only one she actually got to create thanks to her dad. Her main reason for living with her grandma in Foster's Home instead of with her parents? So she could see that same Imaginary Friend she herself created again someday.
Even if she is an Ethnic Scrappy with an annoying singing voice, Eurotrish gets quite a raw deal in "Foster's Goes to Europe". Not only does Bloo keep on rudely denying Eurotrish her chances to go back to Europe, but the scene that plays during the credits shows Eurotrish finally making it to her creator's home, only for her creator to turn her away. It's especially heartbreaking when you take into account that most creators in this series are shown to be loving and caring toward their imaginary friends even in adulthood.