Establishment and maintenance of epigenetic profiles are essential steps of development during which stem cells, despite identical genetic information, will acquire different and selective gene expression patterns, specific for their fate. This highly complex programming process involves mechanisms that are not yet completely understood although it has been established over the past few years that chromatin modifier enzymes (i.e. DNA and histone methyltransferases, histone deacetylases, histone demethy-lases, histone acetyltransferases) play essential roles in the establishment of transcriptional programs accompanying cell differentiation. Investigators in this field have been studying a wide variety of cell types including neural, muscular, mesenchymal and blood cells. This review will focus on epithelial cells of the digestive tract, intestinal stem cell niches being a model of choice to understand how epigenetic changes can drive nuclear programming and specific cell differentiation. Moreover, deregulation of epigenetic programming is frequently observed in human tumours and therefore, decoding these molecular mechanisms is essential to better understand both developmental and cancerous processes.