Chronic increases in brain levels of kynurenic acid (KYNA) in schizophrenia patients are thought to contribute to impaired cognitive function. Here, the authors identify PF-04859989, the first brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II) — the enzyme responsible for brain KYNA synthesis — and demonstrate it to improve cognitive performance under schizophrenic conditions. In rats, systemic PF-04859989 reduced brain KYNA to 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating. The KAT II inhibitor also prevented ketamine-induced impairment of attentional and working memory processes in rodents and non-human primates, respectively.