In healthy cells, mitogenic growth factors signaling through the MAPK pathway trigger sequential phosphorylation and activation of MEK and ERK kinases, which in turn leads to stabilization of Mcl-1, activation of Bcl-2, and degradation of Bim, thereby promoting cell survival. In tumors with B-RAF mutations, B-Raf causes pathway activation independent of upstream signaling by either directly activating MEK1/2 or activating c-Raf, depending on the B-Raf variant present. In this issue of the JCI, Cragg et al. show that MEK inhibitors such as U0126, PD098059, and PD325901 upregulate Bim but do not induce regressions of tumors harboring B-RAF mutations (17). The authors also propose that Bcl-2 and Bcl-x_L neutralize the increased Bim, thereby diminishing the potential apoptotic effect of the MEK inhibitors. Consistent with this model, the authors show that addition of the Bcl-2/Bcl-x_L antagonist ABT-737 enhances the apoptotic effect of MEK inhibition. When Bcl-2 and Bcl-x_L are antagonized, the upregulated Bim binds to Mcl-1, causing it to release Bak and/or Bax, leading to cytochrome c release and subsequent apoptosis. Because tumors with B-RAF mutations are dependent on the MAPK pathway rather than the Akt pathway for survival, combining a MEK inhibitor and a Bcl-2/Bcl-x_L antagonist appears to be a promising strategy for treating these tumors. c-FLIP, cellular FLICE (caspase 8) inhibitory protein; Grb, growth factor receptor–bound protein 2; GSK, glycogen synthase kinase; mTOR, mammalian target of rapamycin; PDK1, phosphoinositide-dependent kinase 1; PH, pleckstrin homology domain; PIP2, phosphoinositol-4,5-bisphosphate; PIP3, phosphoinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; SOS, son of sevenless; XIAP, X-linked inhibitor of apoptosis protein.