Protein geranylgeranylation is critical for the function of a number of proteins such as RhoA, Rac and Rab. Protein geranylgeranyltransferase type I (GGTase-I) and Rab geranylgeranytransferase RabGGTase) catalyze these modifications. In this paper, we first describe identification and chalacterization of small molecule inhibitors of GGTase-I with two novel scaffolds from a library consisting of allenoate derived compounds. These compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein. Derivatizing a carboxylic acid emanating from the core ring of one of the GGTI compounds dramatically improved their cellular activity. The improved GGTI compounds inhibit proliferation of a variety of human cancer cell lines and cause G1 cell cycle arrest and induction of p21CIP1/WAF1. We also report identification of novel small molecule inhibitors of RabGGTase. These compounds were identified first by screening our GGTI compounds for ones that also exhibited RabGGTase inhibition. This led to the discovery of a common structural feature for RabGGTase inhibitors; presence of a characteristic 6-atom aliphatic tail attached to the penta-substituted pyrrolidine core. Further screen led to the identification of compounds with preferential inhibition of RabGGTase. These compounds inhibit RabGGTase activity by competing with the protein substrate. These novel compounds may provide valuable reagents to study protein geranylgeranylation.