Epigenetic mechanisms involving dynamic changes in posttranslational histone modifications commonly control gene transcription and therefore the execution of all cellular differentiation programs. The differentiation of hematopoietic stem cells into specific progenitor cells and the diverse blood cell types represents a particularly powerful system for the study of epigenetic mechanisms. The hematopoietic system allows one to define mechanisms underlying the establishment and regulation of histone modification patterns covering entire genes and/or chromosomes at distinct stages of differentiation. This chapter reviews progress in elucidating principles underlying epigenetic control of complex loci, specifically focusing on genes differentially expressed during hematopoiesis.