The relationship between stem cells and cancer remains poorly understood. Because mouse prostate stem cells preferentially locate in the proximal region of the prostatic ducts, Zhou et al. performed a stage-by-stage evaluation of prostate carcinogenesis associated with p53 and Rb deficiency. Their study demonstrates that all highly aggressive carcinomas originate from the stem/progenitor cell compartment and that neoplastic progression of initiated cells is affected by the prostate microenvironment. These results provide important evidence that p53 and Rb play an essential role in regulation of the prostate stem cell compartment, in which transformation may lead to particularly aggressive cancers. The images on the cover show coexpression (yellow) of cytokeratin 8 (CK8, green) and synaptophysin (red) in putative stem/progenitor cells of the normal prostate (top) and cells of the earliest dysplastic lesion in the proximal region of prostatic ducts in mice with prostate-specific conditional inactivation of p53 and Rb (middle). Cells of dysplastic lesions in the distal region of prostatic ducts express CK8 (green) but not synaptophysin (red; bottom). For details, see the article by Zhou et al. on page 5683 of this issue.