Despite the limitations of the dopamine hypothesis, compelling evidence remains that implicates dysfunction of CNS dopamine systems in the pathophysiology of schizophrenia. The longitudinal measurement of levels of plasma HVA has proved a useful tool in studying neuroleptic effects and has highlighted time-dependent effects as a potentially important facet of the mechanism of antipsychotic action of these drugs. Despite the good clinical correlates of plasma HVA levels, caution is needed in interpreting plasma levels of HVA with regard to CNS dopamine activity. The peripheral nervous system significantly contributes to levels of HVA that circulate in plasma. This issue is underscored by the fact that CSF HVA shows different neuroleptic response patterns than that seen in plasma. The administration of a peripherally acting MAO inhibitor to enhance the CNS "signal" in circulating levels of HVA does not resolve the "problem" of different CSF-plasma HVA neuroleptic response patterns. The possibility that mesocortical dopamine activity is reflected by CSF HVA is suggested by indirect evidence from clinical and preclinical studies. Future studies in which attempts are made at using both plasma and CSF HVA to enhance neurochemical and clinical correlates may help to advance our understanding of the contributions of specific CNS dopamine systems to schizophrenia.