The world of small non-coding RNAs (ncRNA) is continuously expanding, reinforcing the biological importance of these species in both development and disease. Over the past year, our efforts funded by CIRM has been focused on studying the roles of these small ncRNAs in regulating stem cell self-renewal and differentiation. miRNAs are a class of novel, small ncRNAs that negatively regulate global gene expression at posttranscriptional level. Using expression studies, we have characterized the miRNA expression profiles in both ES cells and induced pluripotent stem cells (iPS cells). This effort led to the identification of multiple miRNAs whose levels of expression are either enriched or depleted during stem cell reprogramming. A key finding of the previous funding period is the identification of a family of novel miRNAs that promote differentiation in pluripotent stem cells. This is an important finding because we demonstrated that repression of these miRNAs significantly enhances reprogramming efficiency. miRNAs functions can be modulated by transient transfection of oligonucleotide based antagonist, therefore, our findings are likely to lead to an approach to greatly promote iPSC generation in clinical application. Our future effort in the next funding period (year 3) will be focused on functional characterizations of additional miRNAs in stem cell self-renewal and differentiation and identifying novel ncRNAs that regulate stem cell biology.