Individual cell types are defined by the particular set of genes they express. How is a cell organized so that the right genes are activated at the right time yet silenced at other times? This regulation relies on complex interplay between transcription factors, proteins that bind to regulatory sequences, and the packaging of DNA, which changes with the position and modification of nucleosomes or the methylation of DNA without change in its sequence. We are using mammalian stem cells and their differentiation to defined cell types as cellular models in combination with novel genomics approaches to better understand what generates cell-type specific patterns of transcription and chromatin.