Mice lacking cyclin Dl have been generated by gene targeting in embryonic stem cells. Dyclin Dl-deficient animals develop to term but show reduced body size, reduced viability, and symptoms of neurological impairment. Their retinas display a striking reduction in cell number due to proliferative failure during embryonic development. in situ hybridization studies of normal mouse embryos revealed an extremely high level of cyclin Dl in the retina, suggesting a special dependence of this tissue on cyciin Dl. In adult mutant females, the breast epithelial compartment fails to undergo the massive proliferative changes associated with pregnancy despite normal levels of ovarian steroid hormones. Thus, steroid-induced proliferation of mammary epitheiium during pregnancy may be driven through cyclin Dl.