Catechol-O-methyltransferase (COMT) is a promising target for modulation of cognitive functions and dysfunctions. COMT dominates the regulation of dopamine metabolism in the prefrontal cortex. Thus, COMT effects are particularly evident in prefrontal cortex-dependent cognitive functions including executive control, working memory, attentional control and long-term memory. This has been determined by both genetic and pharmacological studies that we will highlight in the present review. In particular, we will discuss how common functional variants of the COMT gene may predict individual variation in selective cognitive abilities and vulnerability to cognitive deficits that characterize several neuropsychiatric disorders. Moreover, COMT genetic variants represent one source of individual differences in the cognitive responses to medications such as those used in psychiatric illnesses. COMT genetic testing may then predict some cognitive dysfunctions often seen in certain psychiatric illnesses even from presymptomatic stages and the efficacy/dosage of drugs used to treat them. The consideration of COMT-dependent differences may be important for the development of more efficient personalized healthcare.