Conventional histopathologic evaluation of bladder cancer, encompassing tumor grade and stage, is inadequate to accurately predict the behavior of most bladder tumors. Intense research efforts are under way to identify and characterize various bladder cancers and their true biological potential more effectively. The need to predict which superficial tumors will recur or progress--and which invasive tumors will metastasize--has led to the identification of a variety of potential prognostic markers for patients with bladder cancer. The molecular changes that occur in transitional cell carcinoma of the bladder are numerous and can be categorized into (1) chromosomal alterations, leading to carcinogenesis; (2) loss of cell-cycle regulation, accounting for cellular proliferation; and (3) growth control events such as angiogenesis, resulting in metastasis. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumor's phenotype and subsequent clinical behavior. The potential clinical application of new diagnostic techniques (ie, loss-of-heterozygosity analysis to identify tumor suppressor genes) and older, well-established, techniques (ie, immunohistochemistry) combined with improvements in the use of automated and standardized systems are areas of active investigation.