Melanoma is the most aggressive form of skin cancer. The treatment of patients 
with advanced melanoma is rapidly evolving due to an improved understanding of 
molecular drivers of this disease. Somatic mutations in BRAF are the most common 
genetic alteration found in these tumors. Recently, two different 
mutant-selective small molecule inhibitors of BRAF, vemurafenib and dabrafenib, 
have gained regulatory approval based on positive results in randomized phase 
III trials. While the development of these agents represents a landmark in the 
treatment of melanoma, the benefit of these agents is limited by the frequent 
and rapid onset of resistance. The identification of several molecular 
mechanisms of resistance to BRAF inhibitors is rapidly leading to the clinical 
testing of combinatorial strategies to improve the clinical benefit of these 
agents. These mechanisms, and the lessons learned from the initial testing of 
the BRAF inhibitors, provide multiple insights that may facilitate the 
development of targeted therapies against other oncogenic mutations in melanoma, 
as well as in other cancers.