Research in the area of stem/progenitor cells have led to the identification of multiple stem-like cell populations that are implicated in prostate homeostasis and cancer initiation. Given that there are multiple cells that can regenerate prostatic tissue and give rise to prostate cancer, our focus should shift to defining the signaling mechanisms that drive differentiation and progenitor self-renewal. In this article, we will review the literature, present the evidence and raise important unanswered questions that will help guide the field forward to dissecting critical mechanisms regulating stem cell differentiation and tumor-initiation.