Circulating RNAs, especially microRNAs (miRNAs), have recently emerged as non-invasive disease biomarkers. Despite enthusiasm and numerous reports on disease-associated circulating miRNAs, currently there is no circulating miRNA-based diagnostic in use. In addition, there are many contradictory reports on the concentration changes of specific miRNA in circulation. Here we review the impact of various technical and non-technical factors related to circulating miRNA measurement and elucidate the importance of having a general guideline for sample preparation and concentration measurement in studying circulating RNA.