Prostate cancer represents a heterogeneous disease entity with varying degrees of behavior, aggressiveness, patterns of metastasis, and response to therapy. Progressive metastatic prostate cancer is associated with a formidable array of morbidity that ultimately contributes to death of the patient. Thus far, there has been no convincing evidence to support routine use of non-hormonal chemotherapeutic agents or combinations over symptomatic treatment only. Furthermore, no single compound or combination has shown a dramatic improvement in conventional quality of life parameters over symptomatic treatment only. Androgen ablation remains the primary systemic therapeutic modality for this disease, yet the intense delineation of mechanisms involved in tumor cell metastasis has lead to new therapeutic strategies, ranging from cytotoxic to cytostatic, including immunomodulators. Among those strategies currently being studied are granulocyte-macrophage colony-stimulating factor-transduced prostate cancer vaccines, differentiation therapy, gene therapy, inducers of apoptosis, antimetastatic agents, angiogenesis inhibitors, radiation therapy (local and systemic), and systemic approaches targeted at prostate cancer morbidity. The difficult issue is which agents should be developed and how should we best assess the response using standard and newly identified endpoints. Certainly, the future of advanced prostate cancer therapy will undergo dramatic changes as a result of the continued interaction between the laboratory and the clinic.