Relapse is a hallmark of drug addiction and a daunting challenge facing the clinical treatment of the disease. Although the neurobiological mechanisms underlying the rewarding effects of addictive drugs, thought to play a critical role in initiating drug use, have been extensively studied for the past half century, recent research has begun to focus on the neural mechanisms underlying relapse. For the past decade, accumulating evidence indicates that glutamate and dopamine (DA) neurotransmissions in the mesocorticolimbic system are critically involved in this process. This review focuses on the role of the ventral tegmental area (VTA), particularly VTA DA neurons, in relapse, followed by a discussion of synaptic plasticity induced by addictive drugs and the potential role of such plasticity in the risk of relapse. Finally, directions for future research are presented.