Despite a detailed understanding of the molecular aberrations driving the development of urothelial cancers, this knowledge has not translated into advances for the treatment of this disease. Urothelial cancers are chemosensitive, and platinum-based combination chemotherapy remains the standard of care for advanced disease, as well as neoadjuvant and adjuvant therapy for locally advanced disease. However, nearly half of patients who undergo resection of locally advanced urothelial cancer will relapse and eventually develop platinum-resistant disease. Clinical trials of targeted agents against angiogenesis and growth factors, as well as novel chemotheraputics, have generally been unsuccessful in urothelial cancers. Improvements in the theraputic arsenal for urothelial cancer depend upon identification of new targets and strategies to overcome platinum resistance.