Transitional cell carcinoma (TCC) is the fifth most common solid malignancy in the USA. Radical cystectomy will cure a substantial fraction of patients with minimally invasive TCC, but approximately 50% of patients with muscle-invasive or extravesical disease treated by radical cystectomy alone die of metastatic TCC. Transitional cell carcinoma have a diverse collection of biologic and functional characteristics. This is reflected in a differing clinical course. The limited value of established prognosticators, make the analysis of new molecular parameters of interest in predicting the prognosis of bladder cancer patients; in particular, high-risk patient groups that are at risk of progression and recurrence. Over the past decade, there had been major progress in the elucidation of the molecular genetic changes leading to the development of TCC. This review will highlight these important advances and emphasize the ways in which molecular biology is likely to affect the development of future therapies.