Urinary bladder cancer accounts for approximately 5% of all newly diagnosed malignancies in the developed world. Smoking, occupational exposure and dietary factors constitute the most important exogenous risk factors for bladder carcinogenesis. Yet, individuals with seemingly equal exposure to environmental carcinogens develop bladder cancer in an unpredictable manner. This is probably attributed to the fact that DNA repair capacity varies in human populations, pointing the role of genetic susceptibility in human cancer. Numerous studies demonstrated that certain genetic and epigenetic alterations are fairly constant. Loss of heterozygosity (LOH) at chromosome 9 is an aberration found in urothelial cell carcinoma (UCC) of all stages and grades as well as in dysplastic urothelium, possibly representing an early event in urinary bladder carcinogenesis. On the contrary, gains of 3p can only be found in tumors demonstrating highly malignant behavior. Microsatellite instability (MSI) is another frequent finding in urinary bladder cancer. This has led many investigator groups to employ the analysis for MSI for early diagnosis of UCC with promising results. The silencing of certain genes such as p16(INK4A) and DAPK by aberrant methylation of their promoter region also represents an important mechanism in carcinogenesis. Similarly, alterations in certain tumor suppressor genes and proto-oncogenes result in uncontrolled cell proliferation, reduced apoptosis and have been associated with more aggressive UCC phenotypes. Undoubtedly, the application of these observations in clinical practice will make a breakthrough in the management of bladder cancer.