Malignant melanoma, a tumor arising from the transformation of melanocytes, has been increasing in incidence worldwide for the past three decades. Melanoma that has metastasized is usually highly resistant to standard chemotherapy. The standard of care for patients with metastatic melanoma has not changed significantly in the past 20 years, and new strategies for treatment of metastatic melanoma are urgently needed. Significant insights have recently been gained into the molecular events underpinning the development of melanoma. A number of novel compounds designed to target these molecular events, as well as monoclonal antibodies to key immune regulatory functions, have been developed and used in clinical trials. The results of these trials hold great promise for the treatment of subsets of patients with metastatic melanoma.