The book is called the "saddest book I ever read" by Connie Willis' introduction for a reason. The tear jerkers start coming halfway through part 2 through all of part 3.
- Ish's mental breakdown after Joey dies and he realizes that his attempts to preserve knowledge and civilization is a complete failure, and that the conditions of the post-disaster world made it so. "The stars in their courses", indeed
- Ish watching his wife and fellow survivors die, becoming the Last American. The gerational gap between him and the hunter-gatherer culture of his children, grandchildren, and great-grandchildren that have never lived before the plague means that he is without companionship, even in his tribe. The loneliness is almost impossible to imagine.
- The fact that Ish's tribe forgets entirely what the world before was like. It's not just that there is no more scholarship and reading anymore, there is no cultural continuity or tradition of any kind. The tribe has no knowledge of history, they think that the images on coins are old gods. Again, because Ish failed.
- Revisiting the library at the end of parts 2 and 3, when it is clear that nobody will be able to read its books.
- Ish being thought of as a god (somethings he never wanted to become), and not even a very respected god. His people constantly pinch him when he isn't sure how to answer their questions.