Immunotherapy is an effective treatment option for a small percentage of patients with advanced melanoma or at high risk for recurrence after resection of the primary tumor. However, a long period of unsuccessful immune modulation trials involving new cytokines, antibodies, cancer vaccines, adoptive immunotherapy, and combinations generated doubts that benefit could be extended to a larger group of patients. Renewed optimism for the therapeutic potential of immune therapy is currently driven by key advances in tumor immunobiology, including the potential to manipulate and disrupt immune activation checkpoints and tumor defense mechanisms; newer approaches to antigen presentation for immune activation; refinements to procedures for antigen-specific T-cell expansions in vitro and preparative regimens to support their expansion and activity in vivo; gene transfer to alter lymphocyte specificity and function; and the potential for discovery of improved predictive biomarkers to select patients for individual treatments. Proof of concept is provided by durable remissions observed in patients with advanced melanoma enrolled in clinical trials of anti-CTLA-4 and in new studies of adoptively transferred tumor antigen-specific lymphocytes combined with lymphocyte ablation conditioning regimens. Many agents now being developed are predicted to produce broader, more potent, and more effective antitumor immune responses.