Stress may be defined as a sequence of events, that begins with a stimulus (stressor), that is recognized by the brain (stress perception), and which results in the activation of physiologic fight/flight/fright systems within the body (stress response). Many evolutionary selection pressures are stressors, and one of the primary functions of the brain is to perceive stress, warn the body of danger, and enable an organism to respond. We hypothesized that under acute conditions, just as the stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges (e.g., wounding) which may be imposed by a stressor (e.g., an aggressor). Initial studies showed that acute (2h) stress induced a significant trafficking of immune cells to the skin. Since the skin is an organism's major protective barrier, we hypothesized that this leukocyte redistribution may serve to enhance skin immunity during acute stress. We tested this hypothesis using the delayed type hypersensitivity (DTH) reaction, which mediates resistance to various infectious agents, as a model for skin immune function. Acute stress administered immediately before antigen exposure significantly enhanced skin DTH. Adrenalectomy (ADX) eliminated the stress-induced enhancement of DTH while administration of physiological doses of corticosterone and/or epinephrine to ADX animals enhanced skin DTH in the absence of stress. These studies showed that changes in leukocyte distribution and circulating stress hormones are systemic mediators of the immunoenhancing effects of acute stress. We recently identified gamma interferon as a local cytokine mediator of a stress-induced immunoenhancement. Our results suggest that during acute stress the brain sends preparatory warning signals to the immune system just as it does to other fight/flight systems of the body.