Much of our understanding of gene dysfunction in disease comes from the concept of gene mutation or gene deletion. Epigenetic mechanisms, however, can also lead to a functional “knockout” of key disease genes. Among these epigenetic mechanisms is silencing of genes by DNA methylation. DNA methylation in mammalian cells occurs at cytosines residing within CpG dinucleotides. Alterations in developmentally established methylation patterns may alter the gene expression patterns within tissues and cause or promote disease. We are currently studying how methylation patterns are established and the potential for targeting enzymes that establish and interpret methylation patterns with therapeutics.