Addiction to cocaine results from changes in brain function arising from a combination of pharmacology, environmental circumstances, as well as genetic vulnerability. One change is a reduction in Homer protein in the nucleus accumbens. In this report we summarize the behavioral and neurochemical effects of Homer2 gene deletion in mice and compare this with the effects of chronic cocaine treatment in rats. It was shown that Homer2 KO mice demonstrate enhanced locomotor stimulant and conditioned place preference responses to cocaine. Homer2 deletion also caused mice to show reduced basal extracellular glutamate in the nucleus accumbens and a sensitized increase in extracellular glutamate in response to a cocaine injection. In contrast to glutamate, Homer2 KO mice showed a normal increase in extracellular dopamine following a cocaine challenge injection. The parallel between the effect of Homer2 gene deletion and chronic cocaine administration on behavioral and glutamatergic neurochemical responses to cocaine supports involvement of Homer proteins and glutamate transmission in the sensitization of behavior produced by repeated cocaine.