Substance abuse has an enormous impact on economic and quality of life measures throughout the world. In more developed countries, overutilization of the most common forms of substances of abuse, alcohol and tobacco, is addressed primarily through prevention of substance use initiation and secondarily through the treatment of those with substance abuse or dependence. In general, these therapeutic approaches to substance abuse are deemed effective. However, there is a broad consensus that the development of additional tools to aid diagnosis, prioritize treatment selection and monitor treatment response could have substantial impact on the effectiveness of both substance use prevention and treatment. The recent demonstrations by a number of groups that substance use exposure is associated with robust changes in DNA methylation signatures of peripheral blood cells suggests the possibility that methylation assessments of blood or saliva could find broad clinical applications. In this article, we review recent progress in epigenetic approaches to substance use assessment with a particular emphasis on smoking (and alcohol) related applications. In addition, we highlight areas, such as the epigenetics of psychostimulant, opioid and cannabis abuse, which are markedly understudied and could benefit from intensified collaborative efforts to define epigenetic biomarkers of abuse and dependence.