The treatment of metastatic melanomas revolutionized during the past decade because of a better understanding of various pathways and mutations that play different roles in the pathogenesis of this disease. The incorporation of immunotherapy was the first in these efforts, followed by targeted therapies as monotherapeutic options, and then in combinations. In this article, we review the historical and landmark clinical trials that changed our treatment paradigm for advanced melanomas, also we review ongoing clinical trials that would be applicable in the near future and would expectedly improve outcomes for these patients.