An understanding of the biological significance of the multiple genetic alterations identified in clinical bladder cancers to the stepwise pathogenesis of the disease is evolving. Alterations in p53 and pRb, products of the chromosomes 17p13 TP53 and 13q14 RB tumor suppressor genes, occur in approximately 50% and approximately 33% of bladder cancers respectively, and are associated with later stage, higher grade disease. p53 and pRb alterations are also known to occur in early stage bladder carcinoma in situ where they are thought to represent a poor prognosis for tumor progression. Allelic loss of genes on 9p21 occurs in approximately 50% of bladder cancers, but whether the only critical gene in this region is the CDKN2/p16 cyclin/CDK inhibitor is at present uncertain. Amplification and/or overexpression of the oncogenes epidermal growth factor receptor and erbB2 are associated with later stage disease. Finally, recent findings generated using in vitro transformation systems with human uroepithelial cells provide strong evidence that loss of genes on 3p, which occurs in approximately 20% of bladder cancers, and/or gain of genes on 20q play an important role in blocking HUC cellular senescence. This latter phenotype should represent a critical step in oncogenesis, as cells that do not senesce can survive to accumulate the multiple genetic alterations associated with invasive and metastatic bladder cancers. Further understanding of the biochemical mechanisms underlying these genetic changes will provide the additional information needed to design better strategies for bladder cancer intervention and treatment.