Hormone-refractory prostate cancer (HRPC) encompasses a wide spectrum of patients, including patients with prostate-specific antigen (PSA)–only disease, those with increasing PSA levels yet stable metastatic disease, and those with increasing PSA levels and objective evidence of progressive metastases. Unfortunately, with the historical lack of effective therapy in this population, the oncologist is faced with few data with which to make difficult clinical decisions. Although our understanding of the biology of androgen independence continues to improve, and our fund of potential therapeutic agents has widened, multiple trial-specific and patient-specific obstacles have contributed to the difficulty in demonstrating clear benefit to therapy. Herein, we will review the biology of androgen-independent prostate cancer, the historical impediments to clinical trials in this population, and the reasons to treat, or not to treat, the patient with HRPC.