The retinoblastoma (Rb) tumor suppressor controls cellular proliferation, survival, and differentiation and is functionally inactivated by mutations or hyperphosphorylation in most human cancers. Although activation of endogenous Rb is thought to provide an effective approach to suppress cell proliferation, long-term inhibition of apoptosis by active Rb may have detrimental consequences in vivo. To directly test these paradigms, we targeted phosphorylation-resistant constitutively active Rb alleles, RbΔKs, to the mouse mammary gland. Pubescent transgenic females displayed reduced ductal elongation and cell proliferation at the endbuds. Postpuberty transgenic mice exhibited precocious cellular differentiation and β-casein expression and extended survival of the mammary epithelium with a moderate but specific effect on the expression of E2F1, IGF1Rα, and phospho–protein kinase B/AKT. Remarkably, ∼30% RbΔK transgenic females developed focal hyperplastic nodules, and ∼7% exhibited full-blown mammary adenocarcinomas within 15 mo. Expression of the RbΔK transgene in these mammary tumors was reduced greatly. Our results suggest that transient activation of Rb induces cancer by extending cell survival and that the dual effects of Rb on cell proliferation and apoptosis impose an inherent caveat to the use of the Rb pathway for long-term cancer therapy.