The burgeoning area of molecular risk assessment (gene expression profiling and/or proteomic tests) in the diagnosis and treatment of prostate cancer is rapidly illuminating how clinicians might more accurately select the right treatment for the right patient at the right time. Treatment and patient selection and treatment timing form the framework in which clinically available molecular risk profiling tests potentially enhance traditional clinical decision-making. Historically, treatment selection indicated which definitive therapy was chosen (prostatectomy, radiotherapy, etc) and did not include active monitoring of a newly diagnosed patient. Recently, the relative long-term safety of active surveillance (AS) in patients selected based on clinical criteria has been reported. The aforementioned molecular tests have concomitantly been evaluated with respect to the similar, but not entirely equivalent, clinical question: which individual needs treatment? The answer lies in the fact that these tests enable management decisions based on the biologic potential of an individual's tumor, thereby allowing a precision medicine approach to the management of patients with early-stage prostate cancer. Accurate assessment of patients' suitability for AS is important at the population level as well. It is expected that 220,800 cases of prostate cancer will be diagnosed in 2015. Recent analyses have demonstrated that the percentage of these cancers that are low risk and/or with a Gleason score ≤6 ranges from 22% to 50%, and the majority of these patients are likely candidates for AS. However, an estimated 90% of newly diagnosed patients will undergo definitive therapy, highlighting the need to expand AS programs. Herein, we attempted to outline the rationale for the use of molecular risk assessment during counseling of patients regarding AS and posited specific ways in which initial and serial testing might be of value to patients who are managed with AS for increasing lengths of time.