Epigenetic marks are well recognized as heritable chemical modifications of DNA and chromatin that induce chromatin structural changes thereby affecting gene activity. A lesser-known phenomenon is the pervasive effects these marks have on genomic integrity. Remarkably, epigenetic marks and the enzymes that establish them are involved in multiple aspects of maintaining genetic content. These aspects include preserving nucleotide sequences such as repetitive elements, preventing DNA damage, functioning in DNA repair mechanisms and chromatin restoration, and defining chromosomal organization through effects on structural elements such as the centromere. This review discusses these functional aspects of epigenetic marks and their effects on human health and disease.