Research into genetic, psychosocial, and cognitive explanations for depression (biopsychosocial models) provides support for the role of these variables in the etiology of depression. Regularly identified as basic to depression is loss, and the experience of loss has been found to be more influential than genetic factors in the causation of depression. A distinction is drawn between sadness and depression. Sadness is conceptualized as a normal, time-limited response to loss, whereas depression is a disorder because it is recurring and disruptive. Missing from current biopsychosocial explanations for depression is the importance of avoidance behavior in relation to loss. The thesis of this article is that sadness is transformed into depression as a result of avoidance behavior, which blocks access to lost positive reinforcers. Successful treatment requires replacing avoidance behavior with approach behaviors to overcome the consequences of the loss. An equation is presented specifying the factors involved in depression and how they are related. Implications following from the equation fit well with research results. Treatment issues associated with the theory are discussed.