The hypothalamicpituitaryadrenal axis is one of the most important endocrine pathways that coordinate the response of the body to stress, and cortisol is often referred to as the "stress hormone." Although this system is crucial for survival, its chronic activation and high levels of cortisol can have intense neurobiological effects on areas of the brain thought to be involved in mood regulation, cognition, and behavior. This article reviews mechanisms of HPA axis dysregulation, the neuropsychological and physiological consequences of sustained cortisol elevation, and evidence-based strategies to mitigate the effects of cortisol elevations. It should be of general interest to health professionals and to any researcher interested in neuroendocrinology and psychoneuroimmunology.