Metastatic urothelial carcinoma portends a very poor long-term prognosis, with 5-year survival at approximately 5%. The overall survival of metastatic bladder cancer has not improved over the last 20 years. The first-line therapy is cisplatin-based chemotherapy with the response rate approximately 50%. Approximately 30–50% of the patients are unsuitable for cisplatin, and there is no standard of care for this patient population. There is no standard second-line treatment. Several signaling pathways are activated in bladder urothelial carcinoma, but no targeted therapy, either alone or in combination with conventional cytotoxic chemotherapy, has been shown to significantly improve the treatment outcomes. The future of metastatic urothelial carcinoma treatment lies in the ability to deliver personalized therapy. This area remains an active research field today.