The use of standard assessment criteria to evaluate therapeutic responses in patients with advanced prostate cancer is confounded by the high percentage of patients with bone-only metastatic disease. In an effort to develop a reliable means of assessing the activity of various therapeutic interventions, the role of prostate-specific antigen (PSA) as a response parameter is being actively evaluated. The precise role of PSA in this setting remains undefined as there is limited and sometimes conflicting findings in the literature. Additionally, there is emerging data to suggest that various therapeutic agents may influence PSA expression in a manner unrelated to the impact on tumor growth. Given the high percentage of patients with bone metastases, investigators have been actively evaluating a series of new markers of bone turnover; however, the lack of acceptable specificity limits the clinical usefulness of this approach. The role of palliative endpoints such as pain and quality of life measures have been shown to be both feasible and clinically relevant in the assessment of response in patients with symptoms of advanced disease. The emergence of an enlarging subset of asymptomatic patients with PSA-only evidence of metastatic disease presents a new and pressing challenge to clinicians to develop reliable new methods of assessing disease response to therapeutic interventions.