This paper describes recent progress in the design, synthesis and biological evaluation of inhibitors for the enzyme protein farnesyltransferase (PFTase). This enzyme plays a critical role in the post-translational modification of a range of different intracellular proteins. In particular, PFTase attaches a farnesyl group to the GTPase Ras whose oncogenically mutated form is found in over 30% of human cancers. As a result PFTase inhibitors have been developed as potential cancer therapeutic drugs either by rational design based on the structure of the CAAX carboxyl terminus of Ras or random screening of chemical libraries or natural products. Some of these inhibitors show remarkable inhibition potency against PFTase at subnanomolar concentrations and >1000-fold selectivity compared to the related enzyme geranylgeranyltransferase-I. Certain of these compounds are highly effective at blocking the growth of human tumors in animal models and are now undergoing clinical trials. However, several issues in the research remain unsolved, including the mechanism by which PFTase inhibitors suppress tumor growth. Although it has been established that PFTase inhibitors block prenylation of Ras in vitro, the results in whole cells and animal studies suggest the possibility that proteins other than Ras are affected.