Ras proteins play a direct causal role in human cancer and in other diseases. Mutant H-Ras, N-Ras, and K-Ras occur in varyingfrequencies in different tumor types, for reasons that are not known. Other members of the Ras superfamily may also contributeto cancer. Mutations also occur in downstream pathways, notably B-Raf, PTEN, and PI 3′ kinase: These pathways interactat multiple points, including cyclin D1, and act synergistically. In some cases mutations in Ras and effectors aremutually exclusive; in other cases, they coexist. Drugs blocking elements of the pathway are in different stages of clinical development. One of these, the Raf kinase/VEGF-R2 inhibitor Sorafenib, has already been approved for treatment of renal cancerand is being tested in other indications. However, therapeutic targets in the Ras pathway have not yet been fully validatedas bona fide targets.