Two epigenomic targets that potentially link environmental exposures to chemical and physical agents early in development to adult disease susceptibility are imprinted genes and those with metastable epialleles. Genes with metastable epialleles, such as the Agouti locus in the agouti viable yellow (Avy) strain of mice, have highly variable functions because of stochastic allelic changes in the epigenome rather than mutations in the genome. Genomic imprinting is an unique epigenetic form of gene regulation that evolved about 150 million years ago in mammals with the development of the placenta and the advent of viviparity. It results in monoallelic, parent-of-origin dependent gene silencing. Thus, only a single genetic or epigenetic event is required to alter the function of an imprinted gene. The potential importance of these two novel subsets of epigenetically labile genes in the etiology of environmentally-induced diseases will be discussed.