Sca-1 (stem cell antigen-1) enriches for murine prostate cells capable of regenerating tubular structures containing basal and luminal cell lineages in a dissociated cell prostate regeneration system. Sca-1⁺ fractions are enriched for cells at the G₀ stage of the cell cycle, and Sca-1⁺ cells cluster in the proximal region of prostatic tubules where replication-quiescent cells have been localized. Castration-induced enrichment for androgen-independent cells results in a concomitant enrichment for Sca-1⁺ cells. Genetic perturbations of PTEN/AKT signaling in prostate-regenerating cells leads to the initiation of tumorigenesis, and cancer progression is associated with a dramatic increase in Sca-1⁺ cells. Sca-1-enriched prostate-regenerating cells possess multiple stem/progenitor cell properties and can serve as targets for cancer initiation.