Vitamin A (all-trans retinol) and its active metabolites, collectively called retinoids, exert potent effects on stem cell differentiation and thus, the formation of the entire organism, in part via the modulation of the epigenome. All-trans retinoic acid (RA), through binding to the retinoic acid receptors (RARs), alters interactions of the RARs with various protein components of the transcription complex at numerous genes in stem cells, and some of these protein components of the transcription complex then either place or remove epigenetic marks on histones or on DNA, altering chromatin structure and leading to an exit from the self-renewing, pluripotent stem cell state. Different epigenetic mechanisms, i.e. first, primarily H3K27me3 marks and then DNA methylation, may be employed by embryonic stem cells and other stem cells for control of early vs. late stages of cell differentiation. Creating these stable epigenetic changes requires the actions of many molecules, including tet1, polycomb protein complexes (PRCs), miRNAs, DNA methyltransferases (DNMTs), and telomerase reverse transcriptase. A more complete understanding of retinoid-dependent stem cell differentiation should reward us with new insights into the failure to maintain a differentiated state that is an essential part of neoplastic cell transformation and cancer.