The literature on alpha 2-adrenoceptors in depression is replete with seemingly contradictory findings, including reports of both hypersensitive and hyposensitive alterations. Now, with the discovery of nonadrenergic imidazoline receptors (I receptors) and an endogenous I receptor ligand (agmatine), new light is being shed on this controversy. Specifically, those studies that had utilized allegedly "alpha 2-selective" imidazoline radioligands, i.e., 3H-clonidine, could be reinterpreted in terms of increased I receptors in depression. Although the molecular identity of the I1 binding site remains unknown, an I2 receptive site has been reported to be encoded by monoamine oxidase genes (both MAO-A and MAO-B), suggesting a novel explanation for the antidepressant efficacy of idazoxan, a prototypic I2 ligand. Platelet I1 binding sites are also reported to be elevated in patients with unipolar depression and are lowered by antidepressant treatments. Furthermore, clonidine challenge and animal studies of the behavioral effects of imidazolines may be reinterpreted to support a role for I1 sites in the central control of behavior. A hypothesis for depletion of brain clonidine-displacing substance (CDS) in depression is presented. Lowered concentrations of CDS could account for an elevation of I receptors, via compensatory upregulation. Our model offers an explanation for a number of previously discrepant observations as well as testable hypotheses for the study of imidazoline receptors in depression.