Approximately 3 to 5％ of newly diagnosed metastatic cancers are of unknown primary tissue origin due to difficulties identifying a primary tumor using standard diagnostic approaches.MicroRNAs (miRNAs) have recently been demonstrated to be able to assist pathologist with improved accuracy in diagnosing cancers of unknown primary origin (CUP).In this short commentary,we will highlight some of the recent advancements in miRNA based cancer diagnosis as well as some future directions for the field.