Melanoma is a neoplasm with an incidence in the US that is rising at a rate second only to lung cancer in women. Early stage melanoma is curable, but advanced metastatic melanoma is almost uniformly fatal, even in 2003. The close relationship of melanoma with the immune system has led to a recent resurgence in the investigation of immunotherapy in the treatment of this disease. The two most widely investigated immunotherapy drugs for melanoma are interferon (IFN)-alpha and interleukin-2 (IL-2). The role of IFNalpha-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse has recently been established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. Recombinant IL-2 (rIL-2) has an overall response rate of 15-20% in metastatic melanoma and is capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has recently approved the use of high-dose bolus administration of rIL-2 for the therapy of patients with metastatic melanoma. Results of combination chemotherapy and immunotherapy regimens containing rIL-2 and IFNalpha (biochemotherapy) are promising, but conclusions regarding an advantage for this therapy in terms of survival must await the completion of ongoing randomized trials. The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. In the setting of adjuvant therapy, to date, no vaccine has demonstrated a survival benefit in comparison with either observation or IFNalpha. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNalpha.