Prostate cancer and transitional cell carcinoma (TCC) of bladder are the 2 most common malignancies in the male adult urogenital system. Epigenetic gene silencing, particularly tumor suppressor genes, has become a new area of cancer research. Agents such as deoxyribonucleic acid methyltransferase inhibitors or histone deacetylase inhibitors are epigenetic modifiers that can restore gene expression and alter the malignant phenotype of cancer. They provide a new therapeutic avenue for prostate cancer and TCC. It is also likely that combination regimens using epigenetic modifiers with other classes of agents may have higher therapeutic efficacy for prostate cancer and TCC, especially metastatic and/or refractory cases. We review current knowledge of epigenetic event in prostate cancer and TCC, and discuss the possible clinical implications for these 2 diseases.