Prostate cancer screening efforts and early detection of high-risk disease have driven a substantial drop in mortality from the disease, but at the cost of much over-diagnosis and over-treatment of low-risk disease. Indeed, some now believe that the morbidity associated with treatment cause more suffering than the disease itself, leading to calls for the cessation of screening efforts. A better approach is to risk-stratify men with prostate cancer patients with respect to likelihood of progression and, thereby, to personalize care appropriately. This group has been a leader in developing improved clinicopathological stratification tools to help physician and patients predict outcomes and, therefore, make better informed decisions regarding treatment. Further we have been leaders in promoting active surveillance as a viable option to immediate intervention. Through this experience, the need for additional biomarkers to improve risk stratification has becoming increasingly clear. The long term goal is to identify the large number but relatively small proportion of patients with localized disease who will benefit from intervention. Recently, we have validated a tissue RNAbased molecular signature that can significantly add to current clinic-pathological parameters in predicting risk of recurrence. While promising, a more essential need is to identify signatures that can stratify patients prior to intervention as well as follow risk among patient who choose active surveillance. Furthermore, reducing the use prostate biopsy, with its potential side effects, sampling error, and associated high costs would be a major advance for the field. With these issues in mind, we hypothesize that plasma miRNAs could play a major role in improving risk stratification among men with localized prostate cancer. Other recent work of ours has identified a miRNA signature within pre-surgical plasma specimens that improved prediction of post-surgical pathological upgrading over a combination of standard pre-surgical clinical parameters. Here we propose to use recent advances in technologies to expand on these results by performing the following specific aims. First, we aim to validate and expand the plasma miRNA signature associated with pathological upgrading by using newer technology, evaluating a larger population across institutions, and measuring both upgraded and upstaged tumors. Second, we aim to re-validate the signature and to compare tissue, serum, and urine miRNA signatures that predict recurrence among patients who choose intervention. Both aims will be leveraged by performing head-to-head comparisons with current commercially developed tissue/biopsy mRNA signatures already being tested by our group. Third, we will evaluate sequential serum collections on a multiinstitutional cohort of men on active surveillance to evaluate whether the miRNA signature will precede other evidence of progression. Successful completion of this proposal could effect a paradigm shift in patient care as it directly addresses the central problems of whether to treat and how to follow men with localized disease. Such independent prognostic information should decrease suffering associated with care while maintaining the impressive decrease in prostate cancer mortality achieved since the initiation of early detection efforts.