The clinical development of selective BRAF inhibitors for metastatic BRAF V600 
mutant melanoma patients has been a major breakthrough in targeted therapeutics. 
Objective response rates of approximately 50% have been observed in the Phase 
III studies of the BRAF inhibitors vemurafenib and dabrafenib. The side effects 
can be relatively common, including proliferative skin toxicities. The latter 
range from hyperkeratosis and keratoacanthomas (KAs) to squamous cell carcinomas 
(SCCs) and new primary melanomas. In addition, case reports on the emergence of 
gastric/colonic polyps and RAS mutant malignancies have been described during 
BRAF inhibitor therapy. These events have been attributed to paradoxical 
activation of the MAPK pathway in BRAF wild-type cells exposed to selective BRAF 
inhibitors in addition to increased RAS activity. Combined BRAF and MEK 
inhibition appears to improve clinical outcomes and reduce cutaneous 
proliferation events as fewer KAs and SCCs have been observed with combination 
therapy. Next-generation pan-RAF inhibitors ('paradox breakers') and ERK 
inhibitors may further enhance clinical activity in metastatic BRAF-mutant 
melanoma patients and mitigate this paradoxical oncogenesis. Further 
investigation into the potential long-term effects of selective BRAF inhibitors 
is warranted as expanded use of these agents is expected in patients with 
BRAF-mutant melanoma and other malignancies.