Considerable clinical research is focused on improving systemic treatments for melanoma. Unfortunately, the disease is generally resistant to standard chemotherapy, and surgical excision remains the best treatment option whenever possible. However, complete spontaneous regression of melanoma has been observed in some patients, a phenomenon thought to be mediated by the immune system. This has stimulated attempts to manipulate the immune system for therapeutic purposes. Vaccination is a form of active specific immunotherapy, such that the response against the tumor is actively generated by the patient's immune system, and is directed against a particular cellular target or specific membrane antigen. Numerous approaches to vaccination for melanoma have been investigated, and have become more complex as our understanding of anti-tumor immunity has increased. Vaccines have been shown to induce measurable immunologic responses that may be correlated with improved clinical outcomes in patients with melanoma. Large phase III clinical trials using peptide, ganglioside, and whole-cell tumor antigens are ongoing. Although anti-tumor vaccination has shown promising results in patients with melanoma, to date no vaccine has been approved for routine therapy of melanoma. Recently, a phase III trial evaluating the Canvaxin whole-cell vaccine in stage IV melanoma was halted because of a low likelihood of significant benefit. However, a larger phase III trial for patients with stage III disease was continued and results are awaited with interest.