Metastatic melanoma remains a lethal disease with a long-term remission rate of less than 10%. Despite many years of research, there has not been a new drug approved in this disease in over two decades. Single-agent chemotherapy is palliative in some patients and there is no advantage of combination chemotherapy or chemo-immunotherapy in randomized trials. High-dose bolus IL-2 produces some long-term remissions and is available for highly selected individuals at selected centers in the USA but is impractical for most patients. Research is ongoing in exploring novel immunotherapeutic and targeted approaches. The status of recently completed and ongoing trials is discussed in this review.