INTRODUCTION: The clinical activity of BRAF inhibitor (BRAF-I) therapy is a 
major breakthrough in the treatment of metastatic melanoma carrying BRAF 
mutations. However, the therapeutic efficacy of BRAF-I therapy is limited due to 
the onset of intrinsic and acquired drug resistance.
AREAS COVERED: The role of wild-type BRAF in melanocytes and of the mutated BRAF 
in the pathogenesis of melanoma is described in this article. The results 
obtained with BRAF-I in patients with mutated BRAF are reviewed. The mechanisms 
driving the intrinsic and acquired BRAF-I resistance, the development of 
combinatorial strategies designed to overcome them and their potential 
limitations are discussed. Lastly, the many questions that have to be addressed 
to optimize therapy with BRAF-I are listed.
EXPERT OPINION: Melanoma is an aggressive form of skin cancer characterized by 
poor prognosis and high mortality. The discovery of BRAF mutations which drive 
melanoma tumorigenesis and the development of agents which selectively inhibit 
mutant-activated BRAF represent a major breakthrough in the treatment of 
metastatic melanoma. However, the development of drug resistance underlies the 
need of more effective and individualized combinatorial treatments to counteract 
the multiple escape mechanisms utilized by BRAF-mutant melanoma. Although 
combinatorial strategies using agents which target different protumorigenic 
signaling pathway components have been shown to increase the clinical efficacy 
of BRAF-I, novel strategies which utilize different antitumor mechanisms are 
needed.