Prostate cancer is the most frequently diagnosed malignancy in American men. It is the second-leading cause of death, with one in six men having a lifetime risk of diagnosis; however, the therapeutic success rate for prostate cancer is significantly improved by early detection. Over the past three decades, prostate-specific antigen (PSA), a 237 amino acid, 33 kDa, extracellular serine protease, has been used extensively as a serum biomarker to screen for prostate cancer and follow therapeutic responses. In the normal prostate, high concentrations of active PSA are stored in the prostatic collecting ducts1–4 with only small quantities leaking out and forming complexes with its inhibitor, alpha-1 anti-chymotrypsin (ACT), to generate the low nanogram/milliliter levels measured in circulation.5 Prostate cancer cells disrupt this normal tissue architecture resulting in the leakage of increased amounts of PSA into the tissue interstitium and into the circulation, and it has been shown that enzymatically active PSA confers an enhanced growth rate to human prostate cancer cells, indicating a causal role in prostate cancer progression.6 The PSA serum test is simple and inexpensive, and it has been a valuable tool in the detection, staging, and monitoring of prostate cancer. However, the PSA assay has always had a disadvantage in that it is not very specific, detecting common pathological conditions such as benign prostatic hyperplasia (BPH) and prostatitis. Furthermore, in the past decade, the usefulness of PSA as a screening biomarker has become an even more controversial topic with the publication of the results of the Prostate Cancer Prevention Trial (2004) reporting that PSA levels of or less—levels generally thought to be in the normal range—were not rare among the 2950 men with biopsy-detected prostate cancer, including high-grade cancers.7 This has led to increased research using other prostate cancer biomarkers including free PSA, alternative screening tests (transrectal ultrasound), and newer diagnostic antigens, including prostate-specific membrane antigen and prostate cancer antigen 3. The deficiencies in current prostate cancer biomarkers are particularly evident at the level of monitoring disease progression and the outcome of clinical intervention, warranting exploration of new targets and/or methodologies.