As there are no controlled studies on approaches to patients with treatment-resistant psychotic depression many questions remain to be answered. Those that seem worthy of high priority include (1) the efficacy of novel antipsychotic agents (e.g., clozapine, risperidone) for acute and maintenance treatment; (2) the efficacy of newer antidepressant agents such as the SSRIs and nefazodone plus neuroleptic medications; (3) decision trees to delineate the second and third lines of treatment when the first treatment is ineffective; (4) the comparative efficacy of bilateral versus unilateral ECT; (5) the length of time patients should be maintained on medications (which is of particular importance in the case of neuroleptic agents with their potential to cause tardive dyskinesia); (6) the optimal dose of neuroleptic agent for acute treatment; (7) the optimal length of time for medication trials; (8) the use of antidepressant medications during ECT treatments; (9) the importance of the sequence in which TCAs and neuroleptic agents are administered; (10) the delineation of the clinical characteristics of responders to medication versus ECT treatments; and (11) the role of antiglucocorticoid strategies. The answers to these questions would provide clinicians with important tools to treat patients with psychotic depression, an illness that all too frequently can become treatment-resistant.