Funny / The Simpsons: Hit & Run
If you try entering a vehicle from the driver's side that already has a driver in it, they'll notice and make fun of you.
Lisa: Despite my age, I'm the one driving here.
Chief Wiggum: What do you think this is, Grand Theft Auto? Get out there....
Homer: Hee hee! You're dumber than me!
In the opening cutscene:
Announcer: That we know of.
Bart: I've gotta get the new Bonestorm game or I'll be as uncool as Milhouse!
Milhouse: I'm standing right here, Bart.
In Level 2, as Bart is collecting illegal fireworks to join the recent fad, he talks to Moe.
Moe: Sorry, Bart. I can't sell booze to a minor. It ain't right.
Bart: I'm here to buy fireworks.
Moe: Oh, hell yeah!
Pretty much all of Ralph's dialogue in the races.
Apu: Hey, aren't you the boy who nearly drowned in nacho cheese?
Ralph: I was in the newspaper!
In Level 1, one of Homer's missions is to return things to Ned, one of them is a cooler he gave to Barney:
Barney: Now what will I use for a toilet?!?!?
When buying the Plow King from Barney:
Homer: Barney, can I borrow the Plow King?
Barney: Take what you want, you sexy leprechaun, just don't shoot me with that dart gun! Oooooooh....
Mr. Burns initially thinks Homer is a former business partner he murdered: "Wow, that was really...wow."
At the end of level 5, Bart and Apu learn that Buzz Cola is going to send everyone into a murderous frenzy to boost the rating of a reality tv show. Bart's thoughts?
Apu: We must prevent the aliens from putting laser guns in the hands of cola drunk towns people.
Apu: *Facepalms* I tell you what, you're a bad little boy.
The level after, he eventually goes on trying to get help in confronting the matter, with Apu turning chicken and denying that he ever spoke English. After the final mission in Level 6, Bart goes right back to wishing for the worst to happen due to how awesome it would be to him.
After accomplishing Mission 2 of Level 3, you can knock Milhouse into the river (although if you do this beforehand it will prevent you from finishing the mission).
A meta example - Radical Entertainment's devs took an odd glee in having Homer kick Marge around, but were told not to do it around Matt Groening. When Matt was given a chance to test out the game, the first thing he did? Had Homer literally kick Marge from the home down to the Kwik-E-Mart.