On screen, after appearing in recurring roles in television series such as Casualty and The Book Group, he starred as Jesus Christ in the 2003 film The Visual Bible: The Gospel of John. His largest role to date came in 2005 when he was cast as Desmond Hume in the ABC series Lost. Originally a recurring guest star in the second season (for which he received an Emmy nomination), Cusick became a member of the main cast from seasons three to six. Cusick won the role when, while staying at the home of his friend Brian Cox, he met Cox's next-door neighbor, Carlton Cuse, the executive producer of Lost. Cusick stated he believes "a seed (was) planted, because they had been looking for either a Scottish or Irish character."