Since the pioneering studies of Huggins in 1941, it has been known that prostate cancer cells, like certain normal epithelial cells, can chronically depend on a critical level of androgenic stimulation for their continuous growth and survival. The entire issue of the development of resistance to androgen ablation therapy for metastatic prostate cancer is based on the fact that a portion of cells can survive without androgen stimulation. The cell mechanism of androgen independent status is unclear. For some authors, a portion of the cells present within a patient with a prostate cancer before therapy is naturally androgen independent (selection hypothesis). However, this hypothesis does not consider gene alteration during prostate cancer natural history and probably hormone-refractory prostate cancer (HRPC) is due to a multi-step and multi-event process. In this literature review, different cell pathways that lead to HRPC are described.Prostate Cancer and Prostatic Diseases (2001) 4, 204-212.