The ability of many small G-proteins such as RHO and RAL GTPases to contribute to malignant transformation depends on their lipid posttranslational modification by geranylgeranyltransferase-1 (GGT-1). This, coupled with the observation that conditional deletion of GGT-1 compromises KRAS-driven oncogenesis, further spurred interest in the development of GGT-1 inhibitors (GGTIs) as anticancer agents. In this chapter, we describe the development of GGTIs from structure-based drug design to mechanism of action in cultured cells, to antitumor activity in animal models and finally to a recent human phase I clinical trial with GGTI-2418. Highly potent and selective GGTIs inhibit geranylgeranylation of GTPases such as RHOA, CDC42, and RAC1, proteins critical to the G1/S transition of the cell cycle, and induce G1 arrest. This appears to be mediated by induction of p21Cip1, CDK2 and CDK4 inhibition, and RB hypophosphorylation. GGTIs also inhibit CDK2-mediated phosphorylation of p27Kip1 at Thr187, thereby inducing its nuclear accumulation, and this appears to be required for GGTIs ability to induce tumor cell death. Furthermore, suppression of the levels of phospho-Akt, c-FLIP, and survivin as well as induction of death receptors and TRAIL have all been suggested to contribute to GGTIs' ability to induce apoptosis. Extensive work is ongoing to identify proteins whose inhibition of geranylgeranylation contributes toGGTIs' antitumor activity, and the possible involvement of RHOA, RHOC, CDC42, RAC1, RAC3, RALA, and RALB has been suggested.