Background: Occult micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced, muscle-invasive transitional cell carcinoma of the bladder. Objectives: Data supporting neoadjuvant chemotherapy for locally advanced bladder cancer are reviewed. Results: Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy. Trials employing neoadjuvant therapy are particularly valuable in the development of novel systemic therapy regimens, since pathological complete remission appears to be a powerful prognostic factor for long-term survival. Conclusion: Neoadjuvant chemotherapy is a standard for the therapy of locally advanced bladder cancer, and the neoadjuvant paradigm may assist in accelerating novel agent development.