The Raf/MEK/ERK pathway is a conserved signaling module controlling cell growth, proliferation, apoptosis, and differentiation. Constitutive activation of this pathway is involved in malignant transformation by several oncogenes, most notably, Ras. The recent discovery by Davies et al. of somatic mutations in the B-RAF gene in human tumors has generated enormous interest in how Raf kinases are regulated and how mutations in B-RAF lead to transformation. A recent study in Cell by Wan et al. reports the crystal structure of the B-Raf kinase domain, providing important new insights into these questions.