Activating mutations of the BRAF oncogene are present in approximately 5-10% of all human malignancies and lead to constitutive activation of the mitogen activated protein kinase (MAPK) pathway. The introduction of BRAF inhibitors has greatly improved the short term prospects of some patients with these tumors, but the tumors tend to become resistant to therapy with time by activating alternative signaling pathways. Consequently, combination strategies with drugs that block not only the primary mutated BRAF kinase but also the alternative pathways implicated in development of resistance may represent a better strategy for improving survival in patients with tumors harboring BRAF mutations.