- Ladd's rescue of Lua on top of the train.
- Ennis breaking down in tears after meeting Isaac and Miria for the first time. The novels drive it home by stating that this was the first time she had ever genuinely smiled or cried.
- A couple different times with Czes; when he's rescued by the magnificent duo and they tell him he's a good boy, and when he is reunited with Maiza.
Czes: I decided that the entire world, myself included, was just a thing of evil. But why, why are they all so good to me! I feel like I'm the only bad person on earth. You and Maiza and Isaac and Miria and Firo and Ennis and, how, why, you're all... you're all...
- The stake drove down even further in Children of the Bottles. After being tortured for two centuries by Fermet, he devoured his tormentor, inheriting all of Fermet's memories. From these memories he believe that everyone, including himself, are evil. He confess to Elmer that since the Flying Pussyfoot, he's been meeting so many good people. He felt like he's the only bad person.
- This is worse if you remember that, right after Czes was tortured by Claire, he thought that it must have been his punishment for eating a companion, trying to blow up the train, and being immortal. Czes actually knows right from wrong and have a conscience. He's very fast to see other people's kindness, but he doesn't think he's capable of kindness himself, because he believes himself to be bad.
- The ending theme. It will bring tears to your eyes, no matter how lighthearted the series is.
- Nice accidentally blowing herself up. Becomes even more heartbreaking when you realize that she was eight at the time.
- It gets especially tear jerky when Jacuzzi shows up with a gaudy tattoo on his face so his face will stand out like Nice's (which is now permanently scarred) and she won't feel so alone. And then they both cry; Nice because she's so moved, and Jacuzzi because that's just what he does.
- The end of Bullet Garden when Illness breaks down after hearing a hymn of SAMPLE over the phone
- Monicaís death at the end of 1710. The fact that she goes out with a smile after a huge Hope Spot makes it all the worse.
Monica: Thank you, Huey. Goodbye. Letís meet again.
- Barnes' death in the light novels. In the anime, it's mostly just Nightmare Fuel (and a Moral Event Horizon for Szilard), but in the novels we get to read it from his point of view. As his thoughts begin to deteriorate, he tries desperately to remember why he started working on the elixir—unlike Szilard's other elderly lackeys, who mostly did it to avoid growing any older and dying, Barnes did it because he wanted to be seen as a hero. As his thoughts deteriorate further, he mentions something about wanting to save his mother from a man who used to hit her, even though both of those people already died in an accident...and then he forgets who his mother even was as his body is completely consumed.