This article concerns the elaboration of epigenetic models for differentiation. I discuss how results and conclusions arising from studies of prokaryotes were extrapolated to explain differentiation during metazoan development. In this respect, I focus on the presentation of a multi-stable biochemical model by Delbrück in 1949, and on a series of works dealing with enzyme adaptation in Escherichia coli that culminated in Jacob and Monod's operon model. These influential contributions are discussed in the context of debates on nuclear versus cytoplasmic heredity, on the regulation of gene expression, as well as on the mechanisms at the basis of cell differentiation.