Immunotherapy for melanoma has undergone significant change since the first attempts to treat patients with high dose IL-2. Herein, strategies to boost patient antitumor immunity through vaccination, treatment with agents that augment host immunity, and adoptive cell transfer will be discussed. The first two strategies have yielded only limited clinical success, but adoptive cell transfer therapy, particularly following a lymphodepleting, preconditioning regimen has resulted in objective response rates approaching 50%. For a number of reasons, lymphodepletion appears to be critical for maintenance of circulating antitumor T cells following adoptive cell transfer. Balancing antitumor efficacy, autoimmunity, and reconstitution of a functioning immune system remain challenging and potentially life-threatening issues.