Despite major breakthroughs in many areas of medicine over the past 100 years, the successful treatment of cancer remains a significant challenge at the start of the 21st century. The elucidation of molecular mechanisms that promote malignancy is yielding new therapeutic targets for drug discovery efforts. The goal is to produce novel agents that selectively kill tumor cells or inhibit their proliferation without the general toxicity that limits traditional cancer chemotherapy. One wellstudied target is the oncogene ras. Ras proteins are small GTPases that function as on-off switches, regulating cellular functions such as proliferation.1 When the protein binds GTP, it becomes transiently activated but normally reverts to the inactivated GDP-bound state. Ras is mutated in 30% of all human cancers,2,3 and the mutant proteins persistently bind GTP and are constitutively active. It is generally believed that this aberrant function contributes to the development of cancer.1 The discovery that Ras required prenylation for activity led to the targeting of the enzyme responsible, farnesyltransferase (FTase).4,5 Thus, farnesyltransferase inhibitors (FTIs) were conceived as a rational way to treat cancer by inhibiting the function of the oncogene ras. Since they were last reviewed here,6 FTIs have shown efficacy as anticancer agents in clinical trials. At the same time, significant doubt has been cast on a Ras-mediated mechanism of action.