We are taking a systems biology approach in an effort to understand the transcriptional regulatory programs responsible for the making of various cell types. We have developed a series of high throughput methods and computational algorithms for comprehensive mapping of transcriptional regulatory sequences and transcription factor binding in mammalian genomes. Using these tools, we are now examining the gene regulatory networks in human embryonic stem cells in order to understand the processes that control the self-renewal and differentiation of these pluripotent cells. For example, we have already mapped the active promoters, enhancers and insulator elements in human embryonic stem cells and several terminally differentiated cell types. Analysis of the sequences has led to the discovery identifying enhancers as the main driving force that contributes to cell type specific gene expression.