Androgen deprivation therapy (ADT) is now a well-established standard of care in combination with definitive radiotherapy for patients with unfavorable intermediate-risk to high-risk locally advanced prostate cancer. It is also well established that combination modality treatment with ADT and radiotherapy is superior to either of these modalities alone for the treatment of patients with high-risk locally advanced disease. Current treatment guidelines for prostate cancer in the United States are based on the estimated risk of recurrence and death. This review examines the clinical evidence underpinning the use of ADT and radiotherapy among patients with high-risk localized and locally advanced disease in the United States. This review also considers the rationale for moving from traditional luteinizing hormone-releasing hormone agonists to more recently developed gonadotrophin-releasing hormone antagonists. Cancer 2014;120:1620–1629. © 2014 American Cancer Society.