The relationship between dopamine (DA) tone in the prefrontal cortex (PFC) and PFC-dependent cognitive functions (for example, working memory, selective attention, executive function) may be described by an inverted-U-shaped function, in which both excessively high and low DA is associated with impairment. In the PFC, the COMT val158met single nucleotide polymorphism (rs4680) confers differences in catechol-O-methyltransferase (COMT) efficacy and DA tone, and individuals homozygous for the val allele display significantly reduced cortical DA. Many studies have investigated whether val158met genotype moderates the effects of dopaminergic drugs on PFC-dependent cognitive functions. A review of 25 such studies suggests evidence for this pharmacogenetic effect is mixed for stimulants and COMT inhibitors, which have greater effects on D1 receptors, and strong for antipsychotics, which have greater effects on D2 receptors. Overall, COMT val158met genotype represents an enticing target for identifying individuals who are more likely to respond positively to dopaminergic drugs.