The concept of "balanced serotonergic/dopaminergic antagonists" reflects renewed interest in the role of serotonin (5-HT) in schizophrenia. Postmortem brain tissue analysis, cerebrospinal fluid studies, and pharmacological challenges suggest a deficit in 5-HT function in the cortex of patients with schizophrenia. In contrast, however, 5-HT2 antagonism is claimed to have beneficial effects on both positive and negative symptoms of the illness. The authors attempt to resolve this paradox with a model that takes into account the suggestion of a cortical serotonergic hypofunction and a beneficial effect of 5-HT2 antagonism via modulation of subcortical dopamine activity. Although involvement of 5-HT in schizophrenia is supported by compelling evidence, more research is needed to better define its role in pathophysiology and treatment of this illness.