The RAS/RAF/MEK/ERK pathway has been reported to be activated in over 80% of all 
cutaneous melanomas, making it the focus of many scientific studies in the 
melanoma field. Discoveries of mutations and aberrant expression of components 
in this cascade, in particular, BRAF and NRAS render a deeper understanding of 
the mechanisms responsible for oncogenesis and provide new therapeutic 
strategies for this deadly disease. This review starts with a comprehensive 
discussion on the role of this pathway in initiation and progress of melanoma. 
Mechanistically, mutated BRAF and NRAS exert most of the oncogenic effects 
through the activation of the MAPK pathway, which both drive the uncontrolled 
growth of melanoma cells and regulate the cell survival. In a subsequent 
section, clinical efficacy of targeted small-molecule inhibitors is highlighted. 
BRAF-targeted therapies (e.g., vemurafenib, dabrafenib) have showed impressive 
results in systemic therapy for melanoma harboring activating BRAF V600E 
mutations. MEK inhibitors show limited activity in phase I trials, and 
inhibitors directly targeting mutated NRAS, to date, have not been realized. 
Furthermore, the emerging mechanisms underlying both intrinsic and acquired drug 
resistance as well as approaches to prevent or abrogate the onset of therapeutic 
escape are addressed. Finally, the promising vistas and major challenges 
involving small-molecule inhibitors targeting this MAPK pathway in melanoma 
therapy are briefly discussed. It can be envisaged that disseminated melanoma is 
no longer such a bleak prognosis in future given the research and development of 
new signal transduction inhibitors based on our evolving understanding of 
melanoma genetics and intracellular signaling.