Several new agents and combinations demonstrate significant activity in the treatment of patients with hormone refractory prostate cancer. Prostate-specific antigen (PSA) is being used increasingly as the key marker of a therapeutic response in trials of new agents. This article reviews data that support this marker as a surrogate endpoint, and it discusses the issues around the appropriateness of PSA as an intermediate marker with evolving noncytotoxic agents. Other biomarkers of prostate cancer progression are not uniformly elevated in men with advanced disease; to date, they are of limited clinical use. This article also discusses the rationale and results of novel and alternative biomarkers of prostate cancer progression.