Improving our knowledge of the development, course and treatment of major depression is among the most pressing public health concerns in medicine. It is therefore satisfying to observe that critical advances have been made in our fundamental understanding of this illness and related conditions in the past several years. Among the areas of major change have been advances in nosology and disease classification, an improved understanding of risk factors for the development of major depression, advances in the standards of clinical practice, enhanced societal acceptance of patients with the disease and their treatment, and a substantial increase in our understanding of the underlying neurobiology of this common, disabling, and potentially lethal illness. It is sobering, in contrast, to observe that we still use methods of clinical study to explore new treatments with this condition that employ study designs and measurement tools which have changed very little over the past three decades. In this selective review, several key areas of interest relevant to the clinical development of antidepressants are examined. These areas point to some suggested topics for attention in the future.