It has been hypothesized that the negative symptoms of schizophrenia are related to structural brain abnormalities and respond poorly to treatment with neuroleptics and other drugs since they are persistent, if not irreversible. Because this issue has important clinical and theoretical implications, the authors reviewed the relevant literature on the effect of neuroleptics, L-dopa, and other psychotropic agents on these symptoms. Contrary to the above conclusions, several large scale, controlled studies of the therapeutic effects of conventional neuroleptics have reported clinically relevant improvement in negative symptoms in a significant proportion of schizophrenics. The improvement tended to occur early in the course of treatment and was most notable in those patients with relatively shorter durations of illness. A specific class of neuroleptic drugs not studied in these earlier large scale trials, the diphenylbutylpiperidines, has been suggested to be particularly likely to ameliorate negative symptoms, possibly because of their significant calcium channel blocking action. A review of the clinical studies comparing this group of neuroleptics with those from different classes supports the suggestion that they can produce greater improvement in anergia and emotional withdrawal. Six open and four controlled trials of L-dopa treatment of negative symptoms with L-dopa alone or in combination with neuroleptics. As with neuroleptics alone, improvement tended to be greater in those with a shorter duration of illness. The available evidence suggests that negative symptoms, at least in less chronic schizophrenic patients, may be partially responsive to currently available pharmacological intervention in a significant proportion of schizophrenics.