This paper critically reviews empirical findings regarding current key assumptions underlying the nature and treatment of depression which heavily rely on the DSM approach. This review shows that empirical evidence provides little support for these assumptions. In response to these findings, an etiologically based, biopsychosocial, dynamic interactionism model of depression is proposed. This model could foster further integration in research on depression and assist in the development of guidelines for the treatment of depression that are better informed by research findings and more congruent with complex clinical realities.