The discovery of activating BRAF mutations in melanomas has led to the investigation of small molecular inhibitors targeting BRAF mutation and MEK, a downstream protein within the mitogen-activated protein kinase (MAPK) pathway. This article reviews the role of mutant BRAF in melanoma and summarizes the results of clinical trials evaluating inhibitors of BRAF and MEK in BRAF-mutant melanoma. We further describe recent findings on the mechanisms of resistance to BRAF inhibitors and discuss ongoing efforts to combine BRAF inhibitors with other targeted agents. Finally, we review the results of immunotherapy in BRAF-mutant melanoma and address the current status of efforts to either combine or determine the optimal sequence of these two distinct treatment approaches. Although the recent advances in melanoma therapy have been dramatic, greater understanding of melanoma biology coupled with the successful development of several new treatments and combination regimens will further improve patient outcomes in the future.