This review summarizes our current understanding of catechol-o-methyltransferase (COMT) and how it relates to brain function and schizophrenia. We begin by considering the COMT gene, its transcripts and proteins, and its relevance for central catecholamine function. We then describe how variation in COMT activity affects the function of the prefrontal cortex (PFC) and associated areas, reviewing evidence that COMT modulates executive function and working memory and highlighting recent data that also implicate it in emotional processing. Finally, we discuss briefly the genetic association between COMT and schizophrenia, focusing in particular on the complex interaction of functional loci within the gene that may underlie the mixed results of studies to date. We conclude by outlining preliminary data indicating that COMT is a promising therapeutic target for ameliorating the cognitive deficits associated with schizophrenia.