<p>The chemical diversity of histone post-translational modifications (PTMs), or histone marks, has been greatly expanded with the discovery of understudied and emerging modifications. The microbiome and microbial metabolites have been identified as crucial regulators of these novel PTMs, many of which have key roles in gene regulation. Thus, select histone marks represent a mechanism of host–microbe interaction via chromatin. This Perspective details the emerging roles of histone marks in gene regulation and host physiology. We discuss how these PTMs are regulated by microbial metabolism and the molecular mechanisms of how these microbiota-dependent histone PTMs affect host gene expression. We also highlight examples of the functional roles of these histone marks in physiology and disease, with a focus on the intestine and associated tissues. Understanding the mechanistic link between the microbiota and the host epigenome, particularly emerging histone marks, provides new avenues of how microbial metabolites influence host physiology.</p>