Raf kinases function downstream of Ras proteins to activate the MEK-ERK pathway which is deregulated in a large number of human cancers. Raf inhibitors are clinically highly effective for the treatment of cancer and melanoma in particular, but have unexpected side effects that include a paradoxical activation of the ERK pathway. These effects seem to be related to the heterodimerization of Raf-1 and B-Raf kinases. Here, we discuss the role of Raf dimerization as part of the physiological activation mechanism of Raf kinases, the mechanism of Raf dimerization induced by drugs, and the implications of dimerization for drug therapies targeting Raf kinases.