A number of metabolic (e.g., abdominal obesity) and psychological (e.g., depression) pathologies commonly present together and have been associated with dysregulation in the hypothalamo-pituitary-adrenal (HPA) axis. Glucocorticoid hormones represent the final product of this classic neuroendocrine axis, and these steroids modulate neuroendocrine, metabolic, and behavioral function. A primary characteristic of the HPA axis is a negative feedback loop, and glucocorticoids act through the brain to inhibit drive to this neuroendocrine system. Slight and chronic perturbations in glucocorticoid levels, below or above normal, throughout the body lead to metabolic (e.g., abdominal obesity) and behavioral (e.g., depression) pathology. Appropriate feedback in the HPA axis is, therefore, critical, and determining how and where glucocorticoids act to impart their feedback effects have been the focus of many laboratories. However, the answer to these questions remain, in part, elusive. In this chapter, I review findings that have led me to reinterpret glucocorticoid feedback in the HPA axis. I propose that, under basal (nonstress) conditions, glucocorticoid feedback is a consequence of the metabolic actions of the adrenal steroid, not a direct effect on brain. This new perspective may provide insight into the etiology of diseases such as major depression and the metabolic syndrome X, and might explain the commonly observed coexistence of affective and metabolic disturbances.