The abuse of substances such as ethanol, cocaine, amphetamines and heroin is associated with toxic effects on almost every system of the organism. Furthermore, the transition from occasional-recreational use to chronic abuse and addiction is a serious psychiatric disorder with only few chances for effective and definitive treatment since most individuals relapse, even after long periods of abstinence. It is therefore of utmost importance to elucidate the mechanisms by which these substances exert their toxicity and mediate addiction, in order to develop new, efficient therapeutic strategies with a long-term outcome, which are currently lacking. We already know that in a great number of these mechanisms, altered gene function is involved. But, with the new field of epigenetics, there is increasing evidence that changes in the epigenome are responsible for the altered gene function. The advances in the field of epigenetics towards elucidation of the mechanisms underlying toxicity and addiction for ethanol, cocaine, amphetamines and heroin are currently presented and discussed in this review.