The propensity for drug relapse has been associated with cognitive impairments in the prefrontal cortex. Here, the authors examined changes in synaptic plasticity during relapse in a rat model of heroin addiction. They found that there was an increase in the long-term potentiation-like synaptic strength of prefrontal projection neurons that project to the nucleus accumbens, and that this increase was dependent on the recruitment of NR2B-containing NMDA receptors to the cell surface. Furthermore, they found that treatment of addicted rats with the NMDA receptor inhibitor ifenprodil prevented heroin relapse. These findings suggest that NR2B-containing NMDA receptors could represent a novel therapeutic target for addiction.