This presentation approaches the issue of depression in schizophrenia from the standpoint of making a differential diagnosis. This differential includes comorbid medical conditions and side effects of agents used in their treatment; acute or chronic use and/or discontinuation of substances (including "street" drugs, alcohol, nicotine, and caffeine); acute and chronic disappointment reactions; the "negative symptom" syndrome; "depression" as a component of EPS secondary to neuroleptic use, including akinesia and akathisia; the possibility of other dysphoric or anhedonic reactions to neuroleptic medications; depression as an intrinsic component of decompensation, either on a biological or psychological basis; schizoaffective disorder; and the possibility of an independent coexisting affective diathesis. Treatment strategies considered in relationship to these various situations include reducing or otherwise adjusting neuroleptic dosage; changing antipsychotic agents, including the use of "atypical" antipsychotics; the rational use of adjunctive tricyclic, SSRI, and MAOI antidepressant medications; the potential role of benzodiazepines, lithium, anticonvulsants, and ECT; and the importance of psychosocial approaches. An orderly path for considering diagnosis and treatment will be presented.