Neoadjuvant cisplatin-based combined chemotherapy is an established standard for muscle-invasive bladder cancer and pathological complete remission is an excellent intermediate surrogate endpoint for survival. Phase III trials are ongoing to elucidate the role of neoadjuvant combined androgen deprivation and docetaxel-based chemotherapy for localized high-risk prostate cancer. Neoadjuvant therapy with biological agents targeting angiogenesis preceding cytoreductive nephrectomy for metastatic renal cell carcinoma is a novel approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of cytoreductive nephrectomy. Neoadjuvant trials provide a window of opportunity to evaluate and screen novel agents for biological activity by using brief therapy preceding surgery and provide a rationale to further develop the most promising agents in larger trials. The neoadjuvant therapy approach followed by surgery is acceptable and feasible with a wide array of agents in urological cancers and provides a paradigm for evaluating the activity, mechanism of action and resistance to new treatments. Urological cancers are initially characterized by localized presentation in the vast majority of cases, coupled with a substantial risk of distant relapses following surgical resection. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of novel systemic agents and improve outcomes.