Urothelial cancer is the second most prevalent genitourinary malignancy. Up to one-half of patients will relapse even after initial radical surgery. Cisplatin-based chemotherapy, such as the MVAC combination or cisplatin-gemcitabine, can be considered the standard treatment for fit patients with metastatic urothelial cancer. Prognostic factors are the presence of visceral metastasis and a low performance status score. Despite the relatively high response rates obtained with first-line chemotherapy, long-term median survival is low - about 14 months. There is a continuing need to develop more effective chemotherapy regimens and to search for new cytotoxic agents. Only a minority of patients with a major response to chemotherapy may benefit from postchemotherapy surgery. A considerable number of patients have compromised renal function, significant comorbidities, and poor performance status. For these patients, combinations of carboplatin with gemcitabine or gemcitabine with docetaxel or paclitaxel may be an option, but sufficient data from large phase III trials do not exist for this particular clinical setting. Also, only limited data are available regarding the treatment of patients who fail first-line chemotherapy. Based on our growing understanding of the genetic and molecular background of urothelial cancer, new strategies have recently been developed for treating bladder cancer. Several new agents and combinations are currently being evaluated in early clinical trials.