Chronic pain and depressive illness are variably resistant to treatment with current pharmacologic therapies. Pain as a reflex sensory response is accompanied by a fast autonomic and delayed neuroendocrine response mediated by the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis, respectively. The emotional aspect of the pain response is encoded by corticolimbic systems (including the HPA axis) to encapsulate the relationship between pain, memory, and mood. These same systems contribute to the symptomatology of depression, a common symptom of which is pain. Conversely, many chronic pain patients may suffer from depressive illness, which appears to develop as a consequence of chronic pain. A comparison of key changes in HPA function after chronic stress in animals with clinical depression in humans, reveals some striking similarities. In this article, the role of the HPA axis in the etiology of chronic pain and depression is discussed.