Air. Just Air. Especially the "Goal" part, which gets many people every time. Even just showing the video of that scene in an AMV has managed to make them cry. The scene is even more depressing now, when you consider what happened to Misuzu's voice actressa few years later.
The song "Aozora", cued at the highlight of the "Goal" scene, heightens the effect even more, especially with Lia's mournful vocals. Man, they sure unleashed the sadness of the moment in full force, no punches pulled.
The death of Tomoko Kawakami is a Tear Jerker in its own right, especially when you watch the scene.
As if that weren't enough, the penultimate episode had the scene on the beach where Misuzu, about to be taken away from Haruko by her father, cries out for her Mama and runs back to her newly-acknowledged mother. The shift to complete silence instead of screams and tears in the audio only intensified the effect.
Same with Michiru's "death" (or disappearance).
Misuzu's breakdown when she tries playing cards with Yukito.
From the movie, where there isn't a rift between Misuzu and Haruko, you have Haruko trying to convince herself that giving Misuzu back to her father was the right thing to do.