For most of the past 25 years, 1 of the favored approaches to treating prostate cancer has been the suppression of circulating testosterone with luteinizing hormone-releasing hormone (LHRH) agonists. LHRH agonists produce a downregulation of LHRH receptors and an uncoupling of the LHRH signal transduction mechanism. This leads to a marked reduction in the secretion of bioactive hormones stimulating testosterone production and eventual induction of a reversible, but transient and incomplete, state known as “selective medical hypophysectomy.” The treatment with LHRH agonists has proved effective in many settings; however, the dosage and timing strategies depend critically on the patient's disease risk and progression. More recent investigations have suggested that a newer, quicker acting, pure gonadotropin-releasing hormone antagonist might be a preferable treatment approach. It remains a fundamental truth, however, that hormonal therapy is both overused and more toxic than generally appreciated. Therefore, a complete understanding of the indications and applications of this approach is essential for the practice of evidence-based medicine.