Neuropharmacologic discoveries have driven much of the research on neural substances of schizophrenia since the advent of neuroleptic drugs, which appear to share blockade of dopamine receptors. as their common denominator. Yet, despite concerted efforts to identify the source of putative dopaminergic hyperactivity in the brain in schizophrenia, definitive evidence for the "dopamine hypothesis of schizophrenia" remains elusive. More recently, a "neural systems" approach, focussing on the limbic system, has yielded substantial convergent evidence, from both in vivo imaging and postmortem morphological, biochemical, and molecular biological methods, implicating limbic cortex in the neuropathology underlying schizophrenia. Moreover, these limbic cortical regions modulate dopaminergic function in the striatum and nucleus accumbens, via glutamatergic projections. Increasingly, focus is shifting to a role for glutamatergic dysfunction in schizophrenia, opening the possibility that drugs that act upon glutamate function, either directly or indirectly via co-modulators of glutamate transmission, could potentially be developed as adjunctive or primary novel pharmacotherapeutic strategies.