Bladder cancer is the most common malignancy involving the urinary system. Urothelial (transitional cell) carcinoma is a predominant histologic type in Europe, where it accounts for 90 % of all bladder cancers. Much less commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra. Approximately 25 % of patients have muscle-invasive disease and at the time of diagnostics they have either present or later developed metastases. Systemic chemotherapy is a standard approach for patients with inoperable locally advanced or metastatic urothelial malignancies. Although initial response rates are high (about 50 %), the median survival with multiagent chemotherapy is about 15 months. While this is superior to the estimated six-month survival with metastatic disease prior to the development of modern chemotherapy regimens, the five-year survival rate is about 15 % with contemporary regimens. The approach to systemic treatment for metastatic disease of urothelial cancer of the renal pelvis or ureter is based upon results from trials composed primarily of patients with urothelial carcinoma of the bladder. Systemic chemotherapy for metastatic urothelial cancer and the use of chemotherapy as a neoadjuvant or adjuvant combined with cystectomy is reviewed here.