Much interest has developed recently in the use of differentiating agents in the management of solid tumors, specifically prostate cancer. Two classes of drugs that have shown particularly intriguing results are vitamin D(3) and its analogs and the peroxisome proliferator-activated receptor gamma (PPARgamma) ligands. Both the vitamin D(3) receptor and the PPARs are members of the nuclear receptor superfamily of ligand-dependent transcription factors and both are widely expressed by prostate cancer cells. This article reviews in detail the preclinical and clinical data available supporting the use of these agents in the treatment of prostate cancer. The proposed mechanisms of action of these agents and potential future therapeutic roles for these drugs are discussed as well.