In the last two decades, understanding of the dynamics of dopamine function in the prefrontal cortex and its role in prefrontal cortex physiology has opened up new avenues for therapeutic interventions in conditions in which prefrontal cortex function is compromised. Neuropsychological and imaging studies of prefrontal information processing have confirmed specific cognitive and neurophysiological abnormalities in individuals with schizophrenia. Because such findings are also observed in the healthy siblings of patients with schizophrenia, they may represent intermediate phenotypes related to schizophrenia susceptibility genes.Catechol-O-methyltransferase (COMT) represents an important candidate as a susceptibility gene for cognitive dysfunction in schizophrenia because of the unique role this enzyme plays in regulating prefrontal dopaminergic function. A functional COMT polymorphism (Val158Met) predicts performance in tasks of prefrontal executive function and the neurophysiological response measured with electroencephalography and functional magnetic resonance imaging in tasks assessing working memory. In fact, individuals with the Val/Val genotype, which encodes for the high-activity enzyme resulting in lower dopamine concentrations in the prefrontal cortex, perform less well and are less efficient physiologically than Met/Met individuals. These findings raise the possibility of new pharmacological interventions for the treatment of prefrontal cortex dysfunction and of predicting outcome based on COMT genotype. One strategy consists of the use of CNS-penetrant COMT inhibitors such as tolcapone. A second strategy is to increase extracellular dopamine concentrations in the frontal cortex by blocking the noradrenaline (norepinephrine) reuptake system, a secondary mechanism responsible for the disposal of dopamine from synaptic clefts in the prefrontal cortex. A third possibility involves the use of modafinil, a drug with an unclear mechanism of action but with positive effects on working memory in rodents. The potential of these drugs to improve executive cognitive function by selectively increasing dopamine load in the frontal cortex but not in subcortical territories, and the possibility that response to them may be modified by a COMT polymorphism, provides a novel genotype-based targeted pharmacological approach without abuse potential for the treatment of cognitive disorder in schizophrenia and in other conditions involving prefrontal cortex dysfunction.