Prostate cancer is a hormone-dependent, epithelial-derived tumor, resulting from uncontrolled growth of genetically unstable transformed cells. Stem cells are therapeutic targets for prostate cancer, but since disease progression occurs over decades, the imperative is to identify and target the cancer repopulating cell that maintains malignant clones. In order to achieve this goal, we will review the current knowledge of three specific types of cells, their origins, and their differentiation potential. The first is the normal stem cell, the second is the cancer cell of origin and the third is the cancer repopulating cell. Specifically, we review three proposed models of stem cell differentiation in normal tissues, including linear, bi-directional and independent lineages. We consider evidence of the cancer cell of origin arising from both basal and luminal cells. Finally, we discuss the limited data available on the identity and characterization of cancer-repopulating cells in localized and castrate-resistant prostate cancer, which is where we believe the focus of future research efforts should be directed. Ultimately, understanding the intrinsic or extrinsic influences that dictate the behavior of these unique cells will be instrumental in facilitating the development of new therapeutic targets for prostate cancer.