In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction. We show that the orbital cortex is involved in conditioned reinforcement and is thereby important for the acquisition of cocaine-seeking behavior studied in a way that provides an animal experimental homologue of orbital cortex activation and craving upon exposure of addicts to drug-associated stimuli. We discuss the evidence indicating orbital prefrontal cortex dysfunction in human drug addicts, reviewing both neuropsychological and neuroimaging studies. Finally, we consider animal experimental evidence suggesting that addictive drugs may cause orbital cortex dysfunction and thereby contribute to the transition to drug addiction. Reconciling the observations that even brief periods of drug exposure can lead to long-lasting functional and structural deficits associated with the OFC together with those suggesting interactions between a vulnerable phenotype and chronic drug-self-administration will be an important topic of future research.