• Despite renewed interest in negative schizophrenic symptoms, the pathophysiological mechanisms involved in their development remain obscure. Although the cholinergic system has been implicated in schizophrenia, it has not been accorded a major role in current theories of pathophysiology. We present evidence from several lines of research that suggests that muscarinic hyperactivity may be implicated in the pathogenesis of negative schizophrenic symptoms. Specifically, cholinergic overdrive leads to a behavioral syndrome strikingly similar to the negative schizophrenic syndrome, anticholinergic agents may alleviate negative symptoms, schizophrenic patients with negative symptoms tend to "abuse" anticholinergics, and polysomnographic, neuroendocrine, and other pharmacological findings appear to be generally consistent with this hypothesis. The hypothesis is testable and is presented as a heuristic model that focuses on the dynamic interplay between cholinergic and dopaminergic systems in schizophrenia.