All addictive drugs facilitate dopamine transmission, and determining the role of dopamine has been the predominant focus of biomedical research in addiction for 20 years. Newer data and hypotheses have begun to shift our focus to involvement of cortex and corticofugal glutamate projections. The rationale for shifting focus to glutamate ranges from evidence showing that cortical activity is altered in addicts to data from animal models demonstrating drug-induced changes in the function of proteins that regulate pre- and postsynaptic glutamate neurotransmission. Recent studies have particularly focused on involvement of a circuit that includes glutamate projections from the prefrontal cortex to the nucleus accumbens.