Epigenetics is comprised of the stable and heritable (or potentially heritable) changes in gene expression that do not entail a change in DNA sequence. The role of epigenetics in the etiology of human disease is increasingly recognized with the most obvious evidence found for genes subject to genomic imprinting. Mutations and epimutations in imprinted genes can give rise to genetic and epigenetic phenotypes, respectively; uniparental disomy and imprinting defects represent epigenetic disease phenotypes. There are also genetic disorders that affect chromatin structure and remodeling. These disorders can affect chromatin in trans or in cis, as well as expression of both imprinted and nonimprinted genes. Data from Angelman and Beckwith-Wiedemann syndromes and other disorders indicate that a monogenic or oligogenic phenotype can be caused by a mixed epigenetic and genetic and mixed de novo and inherited (MEGDI) model. The MEGDI model may apply to some complex disease traits and could explain negative results in genome-wide genetic scans.