One Last Thing... tells the story of 16 year-old Dylan Jameison (Michael Angarano) who has terminal cancer. When the charitable organization "United Wish Givers" grants Dylan a last wish, he initially chooses to go fishing with his football hero, Jason O'Malley (Johnny Messner). In a moment of inspiration during the locally televised news conference, Dylan changes his mind and reveals that his actual final wish is to spend a weekend with the supermodel Nikki Sinclair (Sunny Mabrey), whose poster hangs proudly above his bed.

Nikki is on the downward slope of self-destruction. In need of a splash of good publicity after pushing another model offstage at the latest fashion show, her agent (Gina Gershon) books a photo op with Dylan, setting the stage for an unlikely "courtship."

With the help of his two best friends, Slap (Gideon Glick) and Ricky (Matthew Bush), Dylan spends his last days in Manhattan, trying to fulfill his wish, to the dismay of his single mom, Karen (Cynthia Nixon). In addition to the usual growing pains encountered by a boy his age, Dylan is faced with coming to terms with his imminent departure from this world. His resulting journey is both touching and surprisingly funny.