Occult distant 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. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. 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, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.