Hormone refractory prostate cancer remains a challenge. While only palliative treatment strategies were available for the past several decades, many promising agents have been investigated over the past decade. Of those the taxanes appeared with significant anti-tumor activity and recently, two large randomized controlled trials demonstrated for the first time, a survival and palliative benefit with docetaxel based chemotherapy. In the current era, recurrent disease after local treatment for localized disease is diagnosed long before evidence of systemic disease. With earlier institution of hormonal treatments, patients are becoming “hormone refractory” earlier in the course of their disease with considerable long life expectancy. Hence, there is a greater need than ever for more treatment options for this expanding group of patients. A number of new systemic therapies have recently emerged, based on a deeper understanding of prostate cancer biology. Novel chemotherapeutics such as the epothilones, molecularly targeted therapies against angiogenesis, the proteosome and endothelin receptor antagonists, as well as biological agents such as anti-sense oligonucleotides are being tested as part of the armamentarium. Key to progress in the therapy of this fatal disease is the commitment and timely enrolment of prostate cancer patients in clinical trials.