Farnesyltransferase inhibitors (FTIs) are potent and selective competitive inhibitors of intracellular farnesyl protein transferase (FTase), an enzyme that catalyzes the transfer of a farnesyl moiety to the cysteine terminal residue of a substrate protein (1). A host of intracellular proteins are substrates for prenylation via FTase, including Ras, RhoB, Rac, membrane lamins, and centromeric proteins (CENPs) that interact with microtubules to promote the completion of mitosis (1–3). Interruption of prenylation may prevent substrates from undergoing maturation, which, in turn, may result in the inhibition of cellular events that depend on the function of those substrates. This finding is the basis for the development of FTIs for therapy of diverse malignancies. This chapter will focus on the current state of knowledge regarding critical molecular targets for FTI action and on the burgeoning application of this class of agents to the treatment of hematologic malignancies, specifically the spectrum of acute and chronic myeloid malignancies and multiple myeloma (MM).