Advanced melanoma has a poor prognosis, and standard adjuvant treatment offers little survival advantage. Current efforts are aimed at combining chemotherapy and novel immunomodulators, which these include melanoma vaccines, cytokines and anti-CTLA4 antibodies. Hundreds of combination therapies are currently in trials. All advanced melanoma patients should be considered for enrollment in a trial for their own benefit as well as for the advancement of melanoma treatment. Thus far, no single investigative approach stands out as highly effective, however, they all hold promise with rare patients showing durable responses. Most treatment protocols are evaluating combinations of adjuvant therapies, hoping to achieve a synergistic effect. Ongoing research into the biology of melanoma continues to suggest new drug targets that will block tumor progression or enhance host response. Until the day that an effective treatment for advanced melanoma is found, prevention and early detection will remain paramount in combating this deadly malignancy.