Tumors with mutant BRAF(V600E) are dependent on ERK signaling for their growth. Unlike MEK inhibitors that suppress ERK signaling in all cells, RAF inhibitors suppress ERK signaling in cells with mutant BRAF, but paradoxically enhance ERK signaling in tumor and normal cells with wild-type BRAF. The mechanistic basis of this phenomenon lies in the interaction of these drugs with RAF dimers. Active RAS promotes homo- and heterodimerization of RAF. Binding of drug to one protomer in the RAF dimer transactivates the other. In BRAF(V600E) tumors, RAS is not activated, RAF is a monomer and thus transactivation is minimal. In these tumors, RAF inhibitors bind to and inhibit the RAF monomer and effectively suppress ERK signaling. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumor activity than MEK inhibitors. Indeed, RAF inhibitors have shown remarkable clinical activity in patients with melanomas that harbor mutant BRAF(V600E), however, resistance invariably develops. The mechanism of action of these drugs suggests that drug resistance could result from any lesion that increases RAF dimerization. These could include mechanisms that increase RAS activation in the tumor cells or lesions that cause RAF to dimerize in a RAF-independent manner. Indeed, mutations in NRAS and activation of receptor tyrosine kinases have now been associated with innate or acquired resistance to RAF inhibitors. We have found that aberrantly spliced forms of BRAF(V600E) are associated with resistance to RAF inhibitors in preclinical models and in patients that relapsed on the RAF inhibitor vemurafenib (PLX4032). These variants lack the RAS-binding domain, constitutively homodimerize in cells with low levels of RAS activity and confer resistance to the drug. Thus, RAF dimerization emerges as a common theme in RAF-inhibitor resistance mechanisms. Since a large part of resistance to RAF inhibitors is attributable to attenuation of the ability of the drug to inhibit RAF, one would predict that such tumors would retain at least partial sensitivity to inhibitors of downstream effectors of RAF such as MEK or ERK. Therefore, combinatorial approaches targeting upstream or downstream of RAF in addition to RAF inhibitors may delay or prevent the onset of these mechanisms of resistance.