Bladder cancer is the second most common genitourinary malignancy in the United States, and is a major cause of morbidity and mortality. Despite aggressive treatment, survival for patients with muscle-invasive urothelial carcinoma of the bladder remains poor. Cancer stage, grade, and other clinical and pathological characteristics provide only limited prognostic information, and there is significant heterogeneity in patient outcomes using current risk stratification. Recent research into the profiling of bladder cancer at the molecular level has begun to shed light on important mechanisms of pathogenesis, as well as providing a number of potential tissue markers. These may provide useful prognostic information and guide patient selection for therapeutic strategies. This review explores recent advances in tissue-based molecular markers in bladder cancer and their potential utility. We also discuss design and statistical consideration for development and validation of molecular markers. A combination of complementary and yet independent molecular markers will likely better capture the biologic potential of each individual bladder tumor resulting in improved clinical decision-making.