This article focuses on the epigenetic alterations of aberrant promoter hypermethylation of genes, and histone modifications or RNA interference in cancer cells. Current knowledge of the hypermethylation of allele(s) in classical tumor suppressor genes in inherited and sporadic cancer, candidate tumor suppressor and other cancer genes is summarized gene by gene. Global and array-based studies of tumor cell hypermethylation are discussed. The importance of standardization of scoring of the methylation status of a gene is highlighted. The histone marks associated with hypermethylated genes, and the miRNAs with dysregulated expression, in kidney or bladder tumor cells are also discussed. Kidney cancer has the highest mortality rate of the genito–urinary cancers. There are management issues associated with the high recurrence rate of superficial bladder cancer, while muscle-invasive bladder cancer has a poor prognosis. These clinical problems are the basis for the translational application of gene hypermethylation in the diagnosis and prognosis of kidney and bladder cancer.