When Sulley says goodbye to Boo. Sulley knows he'll never see her again (he's wrong, but at the time...) but Boo doesn't know that, she's so young and innocent. And that makes it sadder. And it's when she runs up to the door and is ready to burst out to give him another 'scare' but sees the empty closet... oh man that's sad...
Even Roz sounds sympathetic toward Sulley's dilemma.
A "tears of happiness" example: the ending. "Boo?" "Kitty!"
When Sulley accidentally scares Boo. The look on her little face is so heartbreaking... like her world just fell apart. And Sulley'sreaction, as he realizes through Boo's trauma just how he's been appearing to so many children in the past, and just what a terrible thing it is to be "Top Scarer".
Sulley: Did you see the way she... looked at me?
It becomes even worse after you watch Monsters University and you recall what Dean Hardscrabble told him about his scaring.
Just seeing how much the monsters traumatize children, how corrupt Monsters Inc. really is, and how the main characters in the prequel are unaware of that and strive to be a part of said company makes Monsters University a thoroughly depressing watch if you think about it for too long.
The sequence where Sulley thinks that Boo is being horribly killed by the waste disposal. Appropriately, it's a Shout-Out to the Warner Brothers short "Feed the Kitty", where a dog finds a kitten, hides it from his mistress, and goes through the same torment as it appears his mistress is accidentally baking the poor little thing in a batch of cookies. And audiences then lost it too. Both Boo and the kitten were okay.
If Boo crying after Sulley accidentally scared her in that scene wasn't enough, it was the somber-y music playing while she cried. The music shows up earlier after Sulley gets her to go to sleep... try accomplishing two things after listening to it: 1. Try NOT to cry. 2. Try not to picture every scene of Boo, crying or otherwise, accompanied by that music.
Mike's "None of it matters" speech.
Mike: Sulley, what about everything we worked for? Does that matter, huh! And what about Celia? I am never...never going to see her again. Doesn't that matter? What about me? I'm your pal. I'm...I'm your best friend. Don't I matter?
Sulley: I'm sorry, Mike. I'm sorry we're stuck out here. I didn't mean for this to happen, but Boo's in trouble. I think there might be a way to save her if we can just get down to that—
Mike: We? Whoa-whoa-whoa, we? There's no "we" this time, pal. If-if-if you want to go out there and freeze to death, you be my guest. Because you're on your own.
This becomes even more painful if you've seen Monsters University and how hard and long it actually took for them to reach their dream of becoming scarers. Especially with the teasing and put downs by both students and teachers Mike had to suffer with in college because he wasn't good enough to be a scarer no matter how hard he worked at it. To Mike, Sulley was back to being that jerkass back in college that cared about no one but himself.
Depending on your point of view Waternoose is this if you see him as a Jerkass Woobie. He was only driven to villainy out of desperation to keep Monsters, Inc. afloat in the midst of the energy crisis. It's quite heartbreaking seeing him carried away by the CDA accusing Sullivan to be the cause of the energy crisis and that the Monsters Inc will be closed forever thanks to him.