Radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. Although surgery achieves excellent local control, within 5 years almost 50% of patients relapse and subsequently progress to develop systemic disease. Transitional cell carcinoma of the bladder is sensitive to chemotherapy. Although platinum-based chemotherapy can produce relatively high overall response rates, the impact on the survival of patients with advanced disease has, at best, been limited. Randomized trials of cisplatin-based chemotherapy regimens in the neoadjuvant setting have demonstrated the potential to improve survival. By comparison, adjuvant studies have been plagued by suboptimal trial design, limited patient numbers, and lack of standardization of the chemotherapy regimens used. With the introduction of new cytotoxic drugs and novel small molecules, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.