Recurrent melanoma occurs in approximately one third of patients treated for cutaneous melanoma. Although the majority of recurrence occurs within the first few years of primary therapy, a significant number remains at risk beyond 10 years. With rising incidence of recurrent melanoma in Western countries, physicians will undoubtedly face the challenge of managing these patients with the limited therapeutic options currently available. Once melanoma has recurred, the overall prognosis is poor. Localized disease is best treated with complete resection, if indicated. Our existing armamentarium for systemic treatment falls short of altering the course of natural history of melanoma, but regional chemotherapy is an effective modality for in-transit disease and satellitosis. Translational research in molecular genetics and immunology will fuel new ideas for the design of rational strategies toward tumor eradication. Ongoing trials that use gene-modified melanoma cells have begun a new chapter in cancer therapeutics and lend us a closer examination of bench-top science at the bedside.