Prostate cancer screening with PSA and with digital rectal examination isa reality in the United States. Regardless of recent observations regarding the complexities of PSA interpretation, millions of U.S. men expect an annual PSA test and physicians have come to rely on the test, in combination with digital rectal examination, to assess for prostate cancer risk. What has become evident is that PSA can no longer be interpreted dichotomously as a simple yes or no. The test reflects a range of risk and PSA value must be merged with other risk factors of an individual man including ethnicity, family history, as well as the individual's risk aversion to complications from prostate cancer. The future of prostate cancer screening will be built upon incorporation of new biomarkers to the prediction of risk of disease. As these markers move forward in testing, it will no longer be acceptable to move these into clinical usage without formal validation studies and, because of the high frequency of prostate cancer in the general male population, these validation studies will almost certainly have to include measures of prognosis. It is the holy grail of cancer biomarker development to acquire a test that is positive in the man with clinically-aggressive prostate cancer but is negative in both the patient without disease and in the man with disease that will be of no clinical consequence over his lifetime.