Prostate cancer is the most non-cutaneous malignancy diagnosed in men in the USA. The discovery of prostate-specific antigen (PSA) revolutionized prostate cancer diagnosis and management in the 1990s. Despite its remarkable performance as a marker for prostate cancer, PSA is not prostate cancer specific. PSA can be released by normal as well as hyperplastic prostate cells, which undermines the specificity of PSA for prostate cancer diagnosis. Hence, there is a need for new biomarkers that can detect prostate cancer and, in addition, distinguish indolent from biologically aggressive cancers. Moreover, the emergence of new therapeutic approaches for prostate cancer cannot flourish without a more reliable set of markers to serve as prognosticators, targets and surrogate end points of disease progression and response to treatment. As the most useful clinical biomarkers are likely to be those assayed from blood, there is an increasing interest in profiling blood proteins. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation.