Drug treatment of depressive illness in the elderly differs from that in younger patients and there is no clear consensus as to first line treatment in the former. Nor is it possible to extrapolate directly from studies in younger patients to the elderly with these agents. Whilst there are over two dozen antidepressants currently marketed in the U.K., most studies have been on younger adults and have excluded very old and frail patients. Design short-comings of the few trials conducted in elderly patients do not allow accurate interpretation of differences in efficacy or safety between drugs. This paper identifies key deficiencies in the evidence currently available in support of both older and newer antidepressant agents and makes the proposal that specific studies are required in the elderly to determine the efficacy and safety of antidepressants in the treatment of depressive illness. It outlines a Phase II and III clinical trial programme which could be used to provide adequate evidence of efficacy and safety of new agents and which conforms to current European guidelines. Dose finding studies, short-term efficacy, prevention of relapse (continuation therapy) and prevention of recurrence (maintenance therapy) studies are discussed as are key issues to be addressed in the trial protocol.