The discovery that noncoding components of the genome, including microRNA (miRNA or miR), can contribute to the pathogenesis of cancer has led investigators to contemplate using these molecules to guide clinical decision making. Currently, miRNA signatures are being applied in human clinical trials and miRNA-directed therapy is under way, with miR-122 targeting in hepatitis C (HCV) being the most developed therapy thus far. miRNA-based targeting in cancer is not far behind, with several private companies developing therapeutics. We are recognizing the potential for miRNA biology to clarify both the molecular pathogenesis of cancer and the inherent complexities in translating its biology to clinics. An increased understanding of fundamental miRNA biology, improved bioinformatics, and directed in vivo targeting while minimizing off-target effects and toxicity will be required for successful translational application. Here, we provide an overview of miRNAs, with a focus on aspects of translating bench-based discoveries to the clinic.