Differentiation or antiproliferative therapies have been most effective in the treatment of promyelocytic leukemia and are being investigated for the treatment of solid tumors including prostate cancer (PCa). Research suggests that these agents may induce terminal differentiation (arrest in G(0)), induce differentiation to a mature cell with cellular functions and a growth pattern similar to nonmalignant cells, or trigger apoptosis. This review focuses on classes of agents under laboratory and clinical evaluation as antiproliferative or differentiating agents: polyamine inhibitors, vitamin D and its analogs, metabolites of vitamin A, the short-chain fatty acid, phenylbutyrate, and nonsteroidal anti-inflammatory agents. Because differentiation therapies offer a reduced toxicity profile and have potential for preventing or slowing cancer progression, they may offer an alternative to chemotherapy for men with advanced PCa, or may be useful as low-toxicity agents given chronically for chemoprevention in men at high risk for PCa. Clinical trials are needed to define the role of these agents in primary and secondary prevention.