The technique of isolated limb perfusion for treatment of extremity melanoma has been used in the United States for almost 40 years. The treatment is based upon the ability to isolate the circulation of the afflicted extremity from the systemic circulation, thereby allowing dose-intensive delivery of anti-cancer agents to the limb while eliminating systemic exposure and toxicity. A number of agents have been used in ILP, however, the bulk of clinical experience has been with the alkylating agent melphalan, typically used under conditions of mild hyperthermia. Despite considerable clinical experience, there has been a lack of agreement about the role of ILP in the prophylaxis against or the treatment of recurrent extremity melanoma. Recently there has been renewed interest in the use of ILP based upon the very promising results using a combination of tumor necrosis factor, melphalan, and interferon-gamma which have produced complete response (CR) rates of almost 90%. The utility of this regimen in extremity melanoma is actively being evaluated by clinical trials in the United States and Europe.