Advanced urothelial cancer is associated with a poor prognosis and there has been no substantial progress over the past three decades since the development of platinum-based multiagent chemotherapy. Clinical trials evaluating novel agents and combinations including chemotherapeutic drugs, as well as targeted inhibitors, are desperately needed. With a better understanding of the complex molecular alterations that drive urothelial tumorigenesis, new targets for novel therapeutics are being defined. This article will describe the current state of advanced urothelial cancer treatment and provide a comprehensive discussion of novel agents in development.