Damn near every scene involving Jenna having to take crap from her low life husband, especially when he humiliates her at Dawn's wedding.
From the Real Life background: The director, Adrienne Shelly, who also plays fellow waitress Dawn, was murdered by a teenaged construction worker in her house, shortly after the post-production was completed. Such a brilliant film from such a brilliant woman is dampened when one remembers what happened to her.
It doesn't help when you realize that little girl playing Lulu is Adrienne's real life daughter.
In an early scene, Earl tells Jenna she's "no Sara Lee" (a brand of box mix) because she dared to be proud of her pies for five seconds. When Joe suggests she enter the pie contest, she says she won't because "I'm no Sara Lee". She can't even get away from Earl inside her own head.
In general, the situations of the waitresses. Jenna is stuck in an abusive marriage made worse by a pregnancy she never wanted, Becky, like Jenna, is also in a loveless marriage and as a result has turned to an affair just to "remind [her] she's here" and both are, as Dawn puts it, "miserable wives", and Dawn herself has never had a relationship and though she desperately wants one is overwhelmed with fear at the prospect of one.
The utter heartbreak that is "She Used To Be Mine". Earl found the money Jenna has been saving and took it for himself and leaves Jenna to break down and reflect on how different she is from the person she once was and who she is now, that that girl is gone but Jenna used to be her.
It's subtle but there's a part during the line "It's not easy to know I'm not anything like I used to be" where Jenna pauses between the worlds "anything" and "like" making it appears as though Jenna truly doesn't believe she is anything.
She's imperfect, but she tries
She is good, but she lies
She is hard on herself
She is broken and won't ask for help
She is messy, but she's kind
She is lonely most of the time
She is all of this mixed up and baked in a beautiful pie
She is gone, but she used to be mine
Combined with "heartwarming" but Jenna reading Joe's card in which he reveals he's left her his diner and considers her his "only friend" often causes people to wipe away a few tears.
The Cut Song "Without A Believer", in which Dr. Pomatter tells Jenna of his childhood feeling lonely and disregarded by everyone except a waitress who would regularly encourage him to dream big, is one if only for people who didn't exactly have an easy time growing up themselves.