Human embryonic stem (ES) cells have the unique ability to differentiate into nearly any cell type in the human body. During the process of differentiation, ES cells undergo changes in epigenetic structure, such as DNA methylation and post-translational modifications of histones, to bring about changes in gene expression that confer the differentiated state. However, little is known about how the epigenome changes during differentiation. To address this defiency, we have examined the dynamics of chromatin modifications in human ES cells undergoing differentiation into a mesendodermal lineage. We find that while the epigenetic state of promoters remains largely invariant upon differentiation, histone modifications found at enhancers change dramatically. Fascinatingly, a pre-existing epigenetic signature at enhancers in ES cells is indicative of a poised state that may affect differentiation potential. Our results provide new evidence supporting the role of the epigenome in defining enhancers and differentiation.