Melanoma is a malignancy that is highly curable in the early stages but has devastating consequences in later stages due to lack of response to traditional treatments. Improved understanding of the basic science of tumorigenesis has helped lead to novel targeted therapies which are producing beneficial results in patients with melanoma. Enhancement of the immune system by blockade of the cytotoxic T-lymphocyte associated antigen-4 by the monoclonal antibody ipilimumab is now approved by the United States Food and Drug Administration (FDA) for use in patients with unresectable melanoma. The approval of this drug was based on the first ever data in melanoma showing an improvement in overall survival. New advances in targeting components of the mitogen-activated protein kinase pathway are showing impressive responses in clinical trials in most patients harboring activating mutations in BRAF. Thus, this is a new era in the management of melanoma and we review the recent progress made in treating patients with advanced disease.