Franklin: No, worse, he's discouraged. At exactly 10:45 p.m. Earth time, that man will be thinking seriously of throwing away God's greatest gift.
The whole situation where Mr. Gower learned that his son has died. Even the ending where Mr. Gower physically punishes George for not doing his job, only to learn that his grief misguided actions would have accidentally harmed someone. You can't help but cry throughout the whole ordeal.
After Mr. Gower realizes what he's done and how George saved him, he goes to hug George — and George cringes away, begging "Please don't hurt my sore ear again!" The look of absolute horror on Mr. Gower's face seeing that George is afraid of him is painful. Great acting from both of them in this scene.
Heck, George's frustration that he can't escape Bedford Falls throughout the movie is really depressing. This is a guy who just wants to get out and live his life but doesn't leave both out of obligation to those who want to escape Potter and because he has a family of his own. Just when he thinks he has an escape, something happens to get him stuck. James Stewart's performance is just heartbreaking.
The fact that Potter still clings to his greed even as his health is breaking down.
Uncle Billy sobbingly telling George that he's looked all over his house for the missing money, "Even in rooms that have been locked since I lost Laura."
Of worthy mention is the scene where George comes home after learning that Uncle Billy had lost $8000 and takes out his frustration on his family. This seen is especially hard to watch if you've been a kid who has been in a similar situation and thus can relate to George's children. Picture this, you're having a good time with your family without a care in the world (sure. the family didn't have it that great, but the kids seemed happy enough), when suddenly, one or both your parents starts acting angry for reasons you probably can't understand. You don't know how to deal with it, and anything you do will probably make them vent their rage towards you. Relationships get broken, personal belongings may get destroyed, and in worse cases, physical harm may be inflicted upon you. You don't know why all this is happening and all you can do is cry.
Not to mention Mary's reaction when she starts to realize why George is acting the way he is. She gets this terrified look on her face as she starts calling up people for help. Meanwhile, the kids know something is wrong with their father, but no one knows exactly what.
George crying and desperately hugging his child, when he thinks he's going to lose them all, and he doesn't tell them.
George finding Harry's grave in the alternate timeline (pictured above), because of the Fridge Horrorit gives.
For that matter, every second of the alternate timeline. Watching George nervously and desperately trying to find his own life in a world that he was never born into. Trying to find Martini and being outright rejected by Nick, finding his old boss turned into a drunken bum after a jury of his peers mistook a fatal accident for murder, his friends turned on him, his own mother not even recognizing his face, and the love of his life treating him like a lunatic. Watching every piece of his life continually turn out so wrong because he was never there.
Watching Nick callously reject George and throw him and Clarence out of the bar in the alternate timeline is particularly sad when it comes only a short while after Nick in the original timeline (along with Martini) promptly made sure that George was alright after being punched out by Mr. Welch. The two Nicks could not be any more different from each other, much to George's distress.
Clarence sums it all up by dropping this line on George, complete with Title Drop:
Clarence: You see George, you've really had a wonderful life. Don't you see what a mistake it would be to just throw it away?
"Please! Please! I want to live again! I want to live again! I want to live again... please, God, let me live again..." And then the snow starts to fall again.
When George comes back home and is positively insane with the happiness of living, even with the prospect of going to jail. Then his kids show up and he runs up to hug them all. The contrast between this and the way he treated his kids the last time he was home is just beautiful.
At the end, George watches his brother raising a glass to him, singing, and you think about how Harry is only there because of George's existence.
'Dear George, Remember no man is a failure who has friends. Thanks for the Wings!, Love Clarence'