Gene imprinting is an epigenetic mechanism for accomplishing persistent change in gene expression. In this brief paper, we explore the mechanisms for imprinting genes and present data showing that the synthetic estrogen, diethylstilbestrol (DES) can developmentally imprint genes by changing the pattern of DNA methylation. We further discuss the implications of this and other findings for non-mutagenic aspects of developmental toxicology, and suggest ways to use this concept in modifying in vitro screening for developmental toxicants.