It has been suggested that nitric oxide, a nonconventional intra-and intercellular messenger involved in various biological and nervous system functions, may play a crucial role in a sophisticated cerebral microvascular system that regulates cerebral blood flow (CBF) under resting and activated conditions. A review of regional cerebral blood flow (rCBF) studies in schizophrenia shows that in schizophrenia patients this microvascular regulatory system may be deficient, failing to selectively raise rCBF in areas of the frontal and temporal lobes to respond to the physiological load placed on brain cells in these areas during certain neuropsychological tasks. A hypothesis about the more general role of local circuit neurons (LCNs) in the pathophysiology of schizophrenia is revised in light of recent information about both the characterization of LCN subpopulations and the interactions of multiple neuro-transmitter systems in midbrain, striatum, and cortex. This revision helps explain the subtle rCBF regulatory failure, as well as other failures in information processing, in schizophrenia patients and points to interneurons as likely sites for the action of both typical and atypical antipsy-chotic drugs.