The diagnosis, classification, and course of psychotic major depression (PMD) is considered with regard to its status as a distinct syndrome. Several factors, especially biological markers, suggest, although as yet do not confirm, that PMD is distinct from nonpsychotic major depression (NPMD), particularly for the purposes of treatment. This article provides a critical review of somatic treatments for PMD, with attention to problems of inadequate treatment, as well as underused and more recently introduced treatments. The somatic treatment options reviewed include (1) combined antidepressant (AD) and antipsychotic (AP) therapy with tricyclic antidepressants (TCAs) and typical APs; (2) electroconvulsive therapy (ECT); (3) amoxapine; (4) selective serotonin reuptake inhibitors (SSRIs), alone and in combination; (5) several atypical APs, alone and in combination; (6) mood stabilizers and anticonvulsants; and (7) some experimental treatments and surgery. A comprehensive treatment algorithm (heuristic) is presented, which draws on some previous guidelines and the critical review. This heuristic is conservative in its aims, but forward-looking in its recommendations. The status of the TCA plus typical AP regime is challenged as the default first-line treatment, and preferable alternatives are discussed. ECT has been shown to be at least as effective in short-term treatment and should be considered more frequently, especially in severe presentations and as a maintenance treatment. Some single compounds should be considered as first-line monotherapies in less severe cases. For cases in which combined AD+AP regimes are instituted, SSRIs and atypical APs should be used before older classes of drugs are considered. These recommendations aim to minimize the number of treatments used and unwanted effects experienced.