The three main themes in Foer's novel are death, loss, and emotional trauma. There are several deaths alluded to: Oskar's father; Oskar's grandmother's sister, Anna; Ron's wife and daughter; as well as the families of Oskar's grandmother and grandfather during World War II; and the wife of Mr. A. R. Black and the father of Mr. William Black. All the major and most of the minor characters have been affected by death of a loved one. They have all suffered a loss. The story focuses on how they have dealt, or are dealing, with their personal tragedies.

Oskar's experience is the main focus of the novel. He is not doing very well. He is inflicting physical harm to himself in an attempt to either mask or distract from the emotional pain that weighs him down. He is constantly referring to the heavy boots he has been forced to wear since his father died. He is torn between figuring out how his father died and not wanting to know for sure. He listens to his father's final phone messages just to hear his voice, but he hates hearing the desperation. He also admits that there was one other phone call. His father called while Oskar was sitting by the phone, and Oskar refused to answer it. He finds out later that his father had called his mother at work, so Oskar believes that the last phone call was specifically for him. He was not brave enough to pick up the receiver and hear his father's final words.

Oskar's grandfather, after the tragedies he suffered in World War II in Germany, refuses to talk. He also refuses to love. He no longer wants to be attached to anyone, though he cannot completely rid himself of those he has loved. He constantly sees Anna, his true love, in other people. He writes letters to the son he never met. He leaves but must return to his wife, Oskar's grandmother, but as an anonymous "renter." He develops a relationship with Oskar, but he never reveals that he is the boy’s grandfather. Like his hands (one tattooed with the word "yes"; the other with the word "no"), Oskar's grandfather is a man divided.

Oskar's grandmother appears to be functioning better than her husband, though she is, in many ways, one of the more tragic figures. She loves a man whom she knows cannot love her. Then she loses him. She raises a son on her own and then loses him too. Her husband returns, but it is unclear if he or she is in any better condition because of the reunion. They are still cut off from one another and there seems to be no resolution.

Oskar's mother is the biggest mystery. Very little attention is given to her. She remains in the background for most of the story and appears aloof, especially in her relationship with her son. There are moments when she expresses her emotions, allowing Oskar to see that she too is hurting inside. But she appears to have closed up her inner life and for the most part is living on the surface.

Mr. A.R. Black is the epitome of closure from the world. He has not left his apartment since his wife died. He even turns off his hearing aid so as to have one less connection with the world. Oskar reintroduces the world to Mr. Black; and in some ways, Mr. Black does the same for Oskar. In Mr. Black, Oskar discovers someone with whom he can talk.