Muscle-invasive bladder cancer is an aggressive disease with at least 50% of patients dying from metastases within 2 years of diagnosis. The 5-year survival rate for metastatic bladder cancer is <15%. Although modern combination chemotherapy regimens have improved median survival from 6 to 14 months compared with best supportive care, there is still a great opportunity for improvement. New therapies and strategies for better patient and treatment selection are now being investigated for advanced bladder cancer. These include agents that target several pathways involved in the pathogenesis of the disease--such as growth factor receptors, angiogenic pathways, p53, cell cycle checkpoints and apoptosis--as well as novel chemotherapeutic agents. Results from recent and ongoing trials suggest that some of these agents could soon emerge as useful players to overcome the limitations of our present therapies.