Melanoma is the most aggressive of the skin cancers, with historically high rates of morbidity and mortality due to its resistance to traditional cytotoxic therapies. Recently, however, breakthroughs in new therapies have dramatically changed clinical outcomes of this disease. These advances emerged from an improved understanding of tumor oncogenesis and the interacting tumor microenvironment. Small molecules that target the oncogenic mitogen-activated protein kinase (MAPK) pathway, specifically the tyrosine kinase BRAF and its downstream signaling partner MEK, have demonstrated an improved overall survival and progression-free survival for BRAF-mutant melanoma. Additionally, manipulation of tumor immune surveillance by inhibitors of the immune suppressive programmed cell death 1 receptor (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways have recently demonstrated durable responses in various cancers by promoting an anti-tumor immune response. Application of these targeted and immune-modulatory therapies has shown promising outcomes in melanoma. Combinations of these therapies may hold promise to enhance responses further. In this review, we will discuss the current targeted therapies and immunotherapies, and review the results of combination studies and speculate on future treatment paradigms.