A striking feature of schizophrenia is the diversity of the phenomenology both within and between patients. This diversity can be contrasted with the well-circumscribed and stable deficits seen in classic neuropsychological syndromes. The argument will be advanced that the classic lesion model, based on the notion of a segregated deficit, is inappropriate in schizophrenia. Instead the idea will be developed that a more appropriate model is one derived from concepts of neural integration across large-scale brain networks. Empirical data derived from positron emission tomography (PET) within our laboratory that provide support for this suggestion will be presented. One critical observation from these data is a disruption of prefrontal-temporal interactions, under a variety of cognitive activation paradigms, in both chronic medicated and acute unmedicated schizophrenic patients. Furthermore, these data indicate that both regional and interregional neuronal function, including prefrontal-temporal interactions, can be significantly modulated by a neurochemical perturbation of ascending dopaminergic systems. The latter observations suggest that the deficit of abnormal cortico-cortical interactions are to some extent modifiable by neuromodulatory neurotransmitter systems.