Addiction is a chronically relapsing neuropsychiatric disease that occurs in some, but not all, individuals who use substances of abuse. Relatively little is known about the mechanisms which contribute to individual differences in susceptibility to addiction. Neural gene expression regulation underlies the pathogenesis of addiction, which is mediated by epigenetic mechanisms, such as DNA modifications. A growing body of work has demonstrated distinct DNA epigenetic signatures in brain reward regions that may be associated with addiction susceptibility. Furthermore, factors that influence addiction susceptibility are also known to have a DNA epigenetic basis. In the present review, we discuss the notion that addiction susceptibility has an underlying DNA epigenetic basis. We focus on major phenotypes of addiction susceptibility and review evidence of cell type-specific, time dependent, and sex biased effects of drug use. We highlight the role of DNA epigenetics in these diverse processes and propose its contribution to addiction susceptibility differences. Given the prevalence and lack of effective treatments for addiction, elucidating the DNA epigenetic mechanism of addiction vulnerability may represent an expeditious approach to relieving the addiction disease burden.