Stress has been linked to the pathophysiology and pathogenesis of mood and anxiety disorders. Over the past few years, our understanding of the brain and neuroendocrine circuits that are linked to the stress response have increased dramatically. This article reviews a series of animal and human studies aimed at understanding what are the pathways by which stress is perceived, processed, and transduced into a neuroendocrine response. We focus on the classic stress circuit: the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. These studies indicate that the LHPA stress circuit is a complex system with multiple control mechanisms and that these mechanisms are altered in pathological states, such as chronic stress and depression. These studies also suggest that the interactions between the LHPA and other neurotransmitters, such as serotonin, may provide the neurobiological substrate by which stress may affect mood.