Several experimental immunotherapy approaches and standard therapy with high doses of interleukin (IL)-2 can cause prolonged objective responses in some patients with metastatic melanoma. Experimental immunotherapy approaches in clinical development include 1) cytokines such as IL-7 and IL-21, 2) cytokine-antibody fusion proteins or immunocytokines, 3) whole tumor cell vaccines, 4) genetically modified tumor cells, 5) heat shock protein vaccines, 6) peptide vaccines, 7) dendritic cells pulsed with tumor antigens, 8) tumor antigen-naked DNA vectors, 9) recombinant viral vectors (either alone or in a prime boost schedule), 10) adoptive transfer of cloned tumor antigen-specific T cells, 11) Toll-like receptor ligands, 12) antagonistic antibodies to the cytotoxic T-lymphocyte antigen 4 (CTLA4, CD152), and 13) activating antibodies to CD40 and CD137 (41-BB). These improved approaches to induce cytotoxic T-cell responses to tumors are based on a more detailed understanding of the immune system activation and regulation. The higher response rates with modern immunotherapy approaches may allow exploration of the molecular mechanisms that make tumor targets sensitive or resistant to immunotherapy.