Following FDA approval and introduction into the clinic in the mid-1980s, PSA testing has become arguably the most versatile serum tumor marker in urologic oncology with clinical use for early detection (screening) of prostate cancer (PC), risk stratification for clinical staging, prognosis, intermediate biomarker for monitoring tumor recurrence, and more recently as an intermediate biomarker for assessing therapeutic response to antiandrogens, radiation therapy, and chemotherapy. PSA now routinely guides health care providers for the clinical management of PC over a wide range of clinical risk states for men at risk of PC, after local definitive therapy and after systemic therapy to prevent progression to metastatic bone disease, and to palliate men with hormone refractory prostate cancer (HRPC). To further assess the evidence that supports these clinical applications, this commentary reviews and critically evaluates the emerging body of new data focusing on several recently published seminal articles by D'Amico et al and Thompson et al, the new National Comprehensive Cancer Network 2004 recommendations for starting PSA testing at the age of 40 years old, the latest results from 2 phase 3 randomized, controlled trials of taxane-based regimens showing improved survival for men with HRPC, and the recent US FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer that helped to distill and synthesize the current state of the art and the progress toward validation of PSA metrics (eg, PSA velocity) as a surrogate end point (SE) for treatment efficacy with taxane-based regimens. Furthermore, several randomized, controlled chemoprevention trials in progress evaluating agents such as selenium and vitamin E in high-risk cohorts are well poised to confirm the validity of PSA as an SE for clinical efficacy for the prevention and progression of PC. Although there continues to be a need to validate better biomarkers before diagnosis of PC (more sensitive and specific) and after diagnosis to discern between indolent and aggressive forms of PC, it is very likely that some metric of PSA as a biomarker alone or as part of a panel of other serum proteomic markers or tissue-derived multiplex gene expression arrays will be around for years to come as a useful tool for risk stratification, early detection, prognosis, prediction, and as an SE of efficacy for prevention and treatment of PC.