© 2013 by The American Society of Hematology. Complex developmental processes such as hematopoiesis require a series of precise and coordinated changes in cellular identity to ensure blood homeostasis. Epigenetic mechanisms help drive changes in gene expression that accompany the transition from hematopoietic stem cells to terminally differentiated blood cells. Genome-wide profiling technologies now provide valuable glimpses of epigenetic changes that occur during normal hematopoiesis, and genetic mouse models developed to investigate the in vivo functions of chromatin-modifying enzymes clearly demonstrate significant roles for these enzymes during embryonic and adult hematopoiesis. Here, we will review the basic science aspects of chromatin modifications and the enzymes that add, remove, and interpret these epigenetic marks. This overview will provide a framework for understanding the roles that these molecules play during normal hematopoiesis. Moreover, many chromatin-modifying enzymes are involved in hematologic malignancies, underscoring the importance of establishing and maintaining appropriate chromatin modification patterns to normal hematology.