Targeted gene disruption in the mouse germline permits the introduction of gene mutations similar to those found in inherited human diseases. New advances in gene targeting that enable cell type specific gene disruption in mice further increases the utility of mouse models to study genetic defects as found in cancer. Here we review the phenotypes observed in mice carrying germline mutated copies of the retinoblastoma tumor suppressor gene. We will illustrate how methods that permit tissue-specific Rb inactivation in mice provide new and more versatile tools to gain insight into the etiology of sporadic cancer.