- Kyle XY (Matt Dallas): A teen who wakes up in the woods naked and with no memory of his past. He turns out to be a savant and is taken in by the Trager family.
- Nicole Trager (Marguerite MacIntyre): A therapist who has a habit of becoming too attached to her patients. When she brings Kyle home temporarily, it's inevitable that she wants to "keep" him.
- Stephen Trager (Bruce Thomas): Nicole's supportive husband who is the vice-president of a computer company.
- Lori Trager (April Matson): Nicole and Stephen's teen daughter, who is going through her rebellious stage which includes a game of cat and mouse with "bad boy" Declan.
- Josh Trager (Jean-Luc Bilodeau): Nicole and Stephen's young teen son, whose somewhat quick wit is a cover for some insecurities.
- Declan McDunaugh (Chris Olivero): Lori's romantic interest, who is a bit of a bad boy, but grows to earn Kyle's trust.
- Hillary (Chelan Simmons): Lori's best friend; she's all over the map, so it's really hard to describe her as anything other than Lori's confidante.. or foil.
- Amanda Bloom (Kirsten Prout): The Tragers' sweet and intelligent neighbor. She and Kyle quickly bond.
- Charlie (Cory Monteith): Amanda's boyfriend who is suddenly introduced after several episodes.
- Tom Foss (Nicholas Lea): Mysterious man who watches Kyle and seems to know something about what happened to Kyle.
- Professor Kern (Bill Dow): Someone from Kyle's past, who might have had something to do with what happened to Kyle.
- Detective Jason Breen (Kurt Max Runte): Policeman who investigates Kyle's appearance and related discoveries.
