This chapter will review basic and clinical studies of the social, genetic and developmental influences upon the reactivity of the hypothalamic pituitary adrenal (HPA) axis and the relationship of these to depression. Significant advances have taken place in each of these areas and it is now possible to interlink many of these areas of work. In order to do so, this chapter will be organised into five sections. The first section will show how the neuroendocrinology of chronic stress is characterised by an up-regulation of the central drive to the HPA axis in conjunction with down-regulation of its negative feedback control. The second will show that very similar processes occur in depressive illness. The third section will describe social, developmental and genetic influences on the HPA axis both in experimental animals and in man. The fourth will show how activation of the HPA axis can influence the development of animal models of depression as well as the onset and perpetuation of clinical depression. The final section will draw together an overall hypothesis and indicate the potential for new treatments for depression that arise from this work.