A roadblock towards human embryonic stem cell (hESC) based therapy is to generate sufficient amount of differentiated cells for treating a particular disease such as deriving insulin-secreting beta cells from hESC to treat diabetes. This award has funded the development of a new systems biology method that can identify the effective combinations of transcription factors to direct differentiation of hESC into a specific cell type. This method integrates genomic and epigenomic data to infer the connectivity between genes, based on which a genetic network is constructed. A graph model is then applied to this network to reveal the transcription factors that are crucial to decide the cell fate. Experimental validations have confirmed the effectiveness of directed differentiation of hESC to neuronal progenitor cells. The systems biology method developed here is general and can be used to guide directed differentiation of hESC into a cell lineage needed for developing therapeutics.