Eradication of advanced prostate cancer still represents an unsolved clinical problem, making the development of alternative treatment approaches highly desirable. Understanding the molecular alterations that distinguish non-progressive from progressive disease would provide mechanistic information for the identification of new therapeutic targets. Recent findings indicate that human tumors have deregulated expression of microRNAs, which have thus been proposed as novel oncogenes or tumor suppressors. A few studies have analyzed the expression profiles or the functional role of microRNAs in prostate cancer, generating largely inconsistent data. Here we review the major issues that have hindered the identification of prostate cancer-related microRNAs, outlining an approach for rational validation of candidates that might be clinically relevant in the management of this disease.