Chemotherapy may be an appropriate treatment for patients with evidence of disease progression despite of antiandrogen withdrawal or secondary hormonal therapy. But none of the chemotherapeutic regimens, neither monotherapy nor combination therapy, were shown to be superior to another with regard to survival. The criteria to assess the effect of chemotherapy on disease-related symptoms and quality of life is expected to be framed. Preclinical investigations and well-designed, well-powered clinical trials remain key to altering the natural history of hormone-refractory prostate cancer.