It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available antipsychotics fail to improve cognitive and negative symptoms originating from this deficit. Evidence from basic science has revealed the importance of prefrontal dopamine signaling for optimal prefrontal function. This article describes succinctly the progress made so far, taking into account the mechanisms involved in catechol-O-methyltransferase (COMT)-induced modulation of prefrontal dopamine signaling, the impact of COMT on cognitive function and the role of COMT gene polymorphisms. The potential role of the COMT inhibitor tolcapone to improve cognitive function in health and disease is also presented here. It will soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotype-specific, targeted treatments of cognitive and negative symptoms of schizophrenia.