Complex organisms require tissue-specific transcriptional programs, which are acquired during development through the stepwise activation of transcription factor networks acting in tight coordination with epigenetic mechanisms. Recent progresses in genome-wide mapping of various epigenetic marks across a panel of mammalian cell types and developmental stages, together with a multitude of functional analyses, led to significant advances in our understanding of tissue-specific epigenetic regulation of gene expression. These new developments open at last the opportunity to systematically explore the contribution of epigenetics to human disease. © 2013 Springer Science+Business Media New York. All rights are reserved.