RAF kinase inhibitors have substantial therapeutic effects in patients with 
BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the 
therapeutic effects are often temporary. Several mechanisms of resistance to RAF 
inhibitors have been proposed. The majority of these cause ERK signaling to 
become insensitive to treatment with RAF inhibitors by increasing the amount of 
RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant 
RAF. One motivation for studying mechanisms of drug resistance is that such 
efforts may suggest new therapeutic targets or rational combination strategies 
that delay or prevent the emergence of drug-resistant clones. Here, we review 
the current model of RAF inhibitor resistance with a focus on the implications 
of this model on ongoing laboratory and clinical efforts to develop more 
effective therapeutic strategies for patients with BRAF-mutant tumors.