Adult humans harbor at least as many microbial cells as eukaryotic ones. The largest compartment of this diverse microbial population, the gut microbiota, encompasses the collection of bacteria, archaea, viruses, and eukaryotic organisms that populate the gastrointestinal tract, and represents a complex and dynamic ecosystem that has been increasingly implicated in health and disease. The gut microbiota carries ∼100-to-150-times more genes than the human genome and is intimately involved in development, homeostasis, and disease. Of the several microbial metabolites that have been studied, short-chain fatty acids emerge as a group of molecules that shape gene expression in several types of eukaryotic cells by multiple mechanisms, which include changing histone acetylation, inducing DNA methylation, or through microRNA-mediated signaling. Butyric acid, one of the most extensively studied short-chain fatty acids, reaches higher concentrations in the colonic lumen, where it can be used as fuel by healthy colonocytes, than in the colonic crypts, where stem cells reside. In colon cancer cells, which preferentially metabolize glucose by glycolysis, butyric acid induces epigenetic modifications, leading to cell cycle progression inhibition and apoptosis. The lower butyrate concentration in the colonic crypts epigenetically inhibits negative regulators of the cell cycle, pointing towards the importance of the crypts in providing a protective niche for stem cells. A better understanding of the interface between the gut microbiota metabolites and epigenetic changes in eukaryotic cells promises to unravel in more detail processes that occur physiologically and, as part of disease, help develop novel biomarkers, and identify new therapeutic modalities.