Three recently published papers identified multiple mechanisms of RAF inhibitor resistance using cultured cells and patient biopsy specimens (10-12). Nazarian et al., and Villaneuva et al., identified enhanced receptor tyrosine kinase (RTK) signaling, particularly PDGFRβ and IGF1 receptor, as mechanisms of resistance. Nazarian et al., also documented mutational activation of NRAS as an additional mechanism. By ectopic over-expression of cDNAs in sensitive cells, Johanessen et al., identified nine protein kinases as having the ability to confer RAF inhibitor resistance, of which one was a control (MEK1[DD]). Most prominent were the serine kinases COT/TPL2 and CRAF, the former appearing to be responsible for examples of both primary and acquired RAF inhibitor resistance. Johanessen et al., propose that, despite its designation as MAP3K8, COT may be able to directly phosphorylate ERK1/2 in the manner of a MAP2K. Johanessen et al’s observation that over-expressed or mutationally activated CRAF can promote RAF inhibitor resistance echoed observations by Villaneuva et al. that RAF inhibitor resistant cells employ can use either CRAF or ARAF for re-activation of the MEK1/2→ERK1/2 MAP kinase signaling pathway. Proteins implicated in RAF inhibitor resistance are indicated in black.