A wide spectrum of non-protein based biomarkers are under development that promises to revolutionize the care of prostate cancer (CaP) patients. In the context of CaP detection we highlight the potential value of the urine tests PCA3 and Prostarix(TM), especially for their ability to stratify patient risk with previous negative biopsy for occult cancer. The search for such markers is made more complex by the development of MRI and image-fusion technology that can help focus biopsy on specific prostatic lesions. Tissue-gene signatures are finding utility in predicting recurrence and progression after radical prostatectomy or identifying patients with apparent low-risk disease who may harbor occult higher-risk disease that would warrant definitive intervention over active surveillance. Furthermore, serum-based microRNA, cell-free DNA and circulating tumor cells are under investigation in clinical trials, especially in the setting of metastatic castration-resistant CaP, for their ability to predict response to novel therapies and patient survival. The meticulous testing of these biomarkers by incorporation into current clinical trials will aid in their widespread use and ability to guide CaP management.