Many of the brain regions, neurotransmitter systems, and behavioral changes that occur after occasional drug use in healthy subjects and after chronic drug abuse in addicted patients are well characterized. An emerging literature suggests that epigenetic processes, those processes that regulate the accessibility of DNA to regulatory proteins within the nucleus, are keys to how addiction develops and how it may be treated. Investigations of the regulation of chromatin, the organizational system of DNA, by histone modification are leading to a new understanding of the cellular and behavioral alterations that occur after drug use. We will describe how, when, and where histone tails are modified and how some of the most recognized histone regulation patterns are involved in the cycle of addiction, including initial and chronic drug intake, withdrawal, abstinence, and relapse. Finally, we consider how an approach that targets histone modifications may promote successful treatment.