Smoking is perhaps the foremost public health challenge in the United States and in the world. In a series of rapidly emerging studies, we and others have demonstrated that cigarette smoking is associated with changes in the DNA methylation signature of peripheral blood cells. The changes associated with this type of substance use are both dose and time dependent. These changes in DNA methylation are also accompanied by changes in gene transcription and protein expression whose patterns are furthermore indicative of increased vulnerability to other forms of complex illness. In the past, our efforts to translate this knowledge into actionable information has been stymied by a lack of methods through which to systematically to assess these changes. The rapid advance of DNA methylation assessment technologies changes that dynamic and presents the possibility that methylation-based clinical tools to aid the ascertainment of smoking status or effectiveness of treatment can be developed. In this chapter, we will review the latest advances in this field and discuss how these advances allow us insight as to methods through which to prevent smoking and shed insight into optimizing strategies through which to identify biomarkers for other behavioral illnesses which share similar contributions from environmental and gene- environmental interaction effects.