The development of antidepressants that appear to selectively affect either serotonin or norepinephrine has renewed interest in distinguishing neurotransmitter systems and coupling them with clinical phenomenology. Parallel to this development, a number of investigators have documented differences in response to antidepressants among depressive subtypes. For the delusional subtype there is some consensus on the specifics of treatment response. Delusional depression may not respond sufficiently to treatment with antidepressants alone but often requires combination with antipsychotics or electroconvulsive therapy (ECT). It has also become more and more clear that selective serotonin reuptake inhibitors (SSRIs) and some other types of never antidepressants are relatively ineffective for treating depressed inpatients. When treating inpatients, the superiority of tricyclic antidepressants (TCAs) compared to never antidepressants is evident, especially in studies using sufficient doses of TCA. Perhaps most intriguing are the data that suggest that depressed patients of the melancholic (endogenous) subtype does not respond adequately to SSRIs but does respond to TCAs and to ECT. This paper will discuss these aspects emphasizing the Danish University Antidepressant Group studies comparing TCAs and SSRIs.