Although metastatic transitional cell carcinoma of the bladder and urothelium commonly responds to first-line chemotherapy, eventual progression is nearly universal. Current salvage therapy for progressive disease after first-line chemotherapy is ineffective, and such patients are candidates for clinical trials. Neoadjuvant chemotherapy improves long-term outcome and provides an exciting paradigm for the rapid development of systemic therapy. Neoadjuvant chemotherapy with or without radiation also facilitates bladder conservation in patients who attain pathologic complete remission. Definitive data supporting adjuvant chemotherapy are lacking. With the unraveling of bladder cancer biology and the discovery of novel agents targeting several carcinogenic pathways, the future of therapy for transitional cell carcinoma appears promising.