Virtually all patients with hormone-refractory prostate cancer will eventually succumb to their diseases with no demonstrable increase in survival with any second-line therapy, thus making the conventional approach to the treatment of this disease palliative. The Southwest Oncology Group (SWOG) Genitourinary Committee strategy in investigating therapy for hormone-refractory prostate cancer is focused on the application of biologically guided treatments targeting primary patients with limited prior hormonal therapy, taking into account evolving concepts regarding the definitions of "hormone-refractory" disease and response criteria. This report reviews data from selected SWOG studies conducted in the past 10 years, and outlines the rationale and design of current and future studies conducted by the Genitourinary Committee of the SWOG in hormone-refractory prostate cancer.