Conventional frontline cisplatin-based combination chemotherapy with gemcitabine and cisplatin, or traditional or dose-dense methotrexate, vinblastine, doxorubicin and cisplatin, yields high response rates but few durable remissions for advanced urothelial cancer. Salvage therapy is generally disappointing with few responses. A significant proportion of patients exhibit renal dysfunction, entailing carboplatin-based regimens that appear inferior to cisplatin-based regimens, which warrants a special focus In this population. The profusion of novel biologic agents offers the promise of improved outcomes. A multidisciplinary approach is necessary to make therapeutic advances.