Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems.