* 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.
* The series finale. Looks like Mac's moving away! [[spoiler: 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. [[spoiler: 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. Eventually, Mac unleashes a shocking TheReasonYouSuckSpeech... 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 CrowningMomentOfHeartwarming 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 despise you!''' ({{Beat}}) Don't you get it? The populace of this house despises you as well. Basically, I'll make this as quick as possible. You're probably THE epitome of annoying, and no, that's not a good thing. Bloo's name is not Chester, it's Bloo you numbskull! Mr. Herriman is not a badger, you play checkers oddly, and protein doesn't come from bananas, it comes from nuts, which you don't need to eat more of because you're a nutcase! 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 the spawn of Satan and wants you to go back to South Park!!!'''
* 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.