We describe the design of a potent and selective peptidomimetic inhibitor of geranylgeranyltransferase I (GGTI), GGTI-2418, and its methyl ester GGTI-2417, which increases the levels of the cyclin-dependent kinase (Cdk) inhibitor p27^Kip1 and induces breast tumor regression in vivo. Experiments with p27^Kip1 small interfering RNA in breast cancer cells and p27^Kip1 null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27^Kip1. GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27^Kip1 at Thr187 and accumulates p27^Kip1 in the nucleus. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. Furthermore, in ErbB2 transgenic mice, GGTI-2418 increases p27^Kip1 and induces significant regression of breast tumors. We conclude that GGTIs' antitumor activity is, at least in part, due to inhibiting Cdk2-dependent p27^Kip1 phosphorylation at Thr187 and accumulating nuclear p27^Kip1. Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27^Kip1 levels.