Inhibition of farnesyltransferase (FTase) has been thoroughly investigated as a strategy to discover novel anticancer drugs because the oncoprotein Ras, requires farnesylation for its cancer-causing activity. Several highly potent and selective FTase inhibitors have been made and show excellent antitumour activity against human tumours in animal models without toxicity to normal cells. However, resistance of the most frequently mutated form of Ras, K-Ras, to FTase inhibitors and its alternative prenylation by geranylgeranyltransferase I (GGTase I), has cast doubts on whether K-Ras is the target for FTase inhibitors. This monthly update focuses on issues of critical importance to the further development of FTase inhibitors as anticancer agents. Alternative prenylation of K-Ras by GGTase I as a mechanism of resistance to FTase inhibitors, targets for FTase inhibitors other than K-Ras and the relevance of GGTase I inhibitors as antitumour agents will be discussed.