The effectiveness of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) were contrasted in endogenous/melancholic depression. By reviewing Hamilton Depression Rating data from controlled trials, the data indicate that TCAs are consistently more effective than the SSRIs. Despite the wide use of SSRIs in the treatment of depression, it seems reasonable that clinicians subtype their depressed patients and treat melancholic patients first with a course of TCAs. For melancholic patients who have not responded to a SSRI, pharmacotherapeutic alternatives include (1) a TCA alone; (2) TCA augmentation of the SSRI, or (3) lithium augmentation of the SSRI.