Most biological processes, including diseases, involve genetic and non-genetic factors. Also, the realization of a genetic potential may depend on environmental factors by directly affecting the expression of gene(s). Exactly how different environmental factors affect gene expression is not well understood. One of the mechanisms may involve DNA methylation and thereby gene expression. Diet, chemicals, and metals are known to affect DNA methylation and other epigenetic processes but are just beginning to be elucidated. For example, methylation of cytosine(s) in the promoter region could prevent the binding of transcription factors or create binding sites for complexes that deacetylate neighboring histones that in turn compact the chromatin, encouraging a gene to become silent. This article will discuss DNA methylation as an epigenetic mechanism of gene regulation and examine how factors like diet, chemicals, and metals may affect DNA methylation. The effect of alterations in DNA methylation may include aberrant expression of genes or genomes and chromosomal instability, which in turn may contribute to the etiology of complex multifactorial diseases. A similar mechanism is now recognized in a number of cancers. There is also indirect evidence to suggest that methylation could apply to a number of complex diseases, including schizophrenia.