The main contributors to the search for functional brain changes in schizophrenia in the past years have employed imaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). Our laboratory has applied a novel strategy involving the post-mortem measurement of the mitochondrial respiratory chain enzyme cytochrome-c-oxidase (COX) to address the question of regional metabolic changes in schizophrenia. This approach is based upon a strong body of evidence which indicates that neuronal COX is highly regulated by the energy demands of the cell and as such represents an endogenous marker of cellular energy metabolism over time. Our original findings indicated that COX activity may be reduced in the striatum and frontal cortex consistent with the concept that a state reduced activity in cortico-striatal circuits may underlie schizophrenia. Subsequent studies from our laboratory on the effects of neuroleptics, PCP, and methamphetamine on animals, have provided additional evidence that a state of dopaminergic overactivity or glutamatergic underactivity produces a hypometabolic state similar to that which is evident in the brains of schizophrenics.