Melanoma is an aggressive form of skin cancer that causes the greatest number of 
skin cancer-related deaths worldwide. In its early stages malignant melanoma can 
be cured by surgical resection, but once it has progressed to the metastatic 
stage it is extremely difficult to treat and does not respond to current 
therapies. A majority of cutaneous melanomas show activating mutations in the 
NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal 
transduction pathway. The discovery of activating BRAF mutations in ∼50% of all 
melanomas has proved to be a turning point in the therapeutic management of the 
disseminated disease. This review summarizes the critical role of BRAF in 
melanoma pathophysiology, the clinical and pathological determinants of BRAF 
mutation status and finally addresses the current state of the art of BRAF 
inhibitors. We further outline the most recent findings on the mechanisms that 
underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing 
preclinical and clinical studies designed to delay or abrogate the onset of 
therapeutic escape.