Eight members from two generations of a family met the DSM-III-R criteria for major depression. Four individuals had severe prolonged depressive disorders that did not respond to standard therapeutic doses of tricyclic and new generation antidepressants, but subsequently responded to the monoamine oxidase inhibitor, tranylcypromine. The literature on pharmacogenetics of the antidepressants is sparse. The pattern of selective response to tranylcypromine in this family supports the view that there is a familial tendency to respond to specific antidepressants or antidepressant groups. A history of response to a specific antidepressant in a relative may be helpful when selecting an antidepressant. Families demonstrating preferential response to specific psychotropics may be suitable pedigrees in which to perform linkage analysis using candidate genes related to the site of action of that psychotropic drug.