A hallmark of drug addiction is the uncontrollable desire to consume drugs at the expense of severe negative consequences. Moreover, addicts that successfully refrain from drug use have a high vulnerability to relapse even after months or years of abstinence. In this chapter, we will discuss the current understanding of drug-induced neuroplasticity within the mesocorticolimbic brain system that contributes to the development of addiction and the persistence of relapse to drug seeking. I particular, we will focus at animal models that can be translated to human addiction. Although dopaminergic transmission is important for the acute effects of drug intake, the long-lived behavioral abnormalities associated with addiction are thought to arise from pathological plasticity in glutamatergic neurotransmission. The nature of changes in excitatory synaptic plasticity depends on several factors, including the type of drug, the brain area, and the time-point studied in the transition of drug exposure to withdrawal and relapse to drug seeking. Identification of drug-induced neuroplasticity is crucial to understand how molecular and cellular adaptations contribute to the end stage of addiction, which from a clinical perspective, is a time-point where pharmacotherapy may be most effectively employed. © 2012 Springer-Verlag/WIen.