It is now well accepted that the immune and nervous systems participate in bidirectional communication. The nervous system has been shown to modulate immune function via its regulation of neuroendocrine secretions and autonomic neural activity. Conversely, cytokines released from immune cells appear to modulate nervous system function via passage at the circumventricular organs, binding to sites on the cerebral vasculature or active transport across the blood-brain behavior. The two systems work together during the challenge and stress of infection to activate local inflammatory responses to eliminate invading pathogens as well as to terminate inflammation and restore host homeo-stasis. It has also become increasingly clear that regulatory mechanisms within the adrenal gland itself, including neural input and adrenal production of cytokines, contribute significantly to adrenal gland function. Further, exposure to stressful events can result in sensitization of various neuronal and hormonal responses that include different brain circuits including the hypothalamus and hippocampus. Also, a neural pathway termed the cholinergic anti-inflammatory pathway has been described that reflexively contributes to the inflammatory immune response by inhibiting pro-inflammatory cytokine synthesis. The acetylcholinesterase gene via alternative splicing gives rise to an isoform of the enzyme found predominately during stress-associated disorders. Numerous pathways, therefore, involving cytokines along with both central (emotional stimuli) and peripheral (immune stimulation) components appear to be involved in stress sensitization of the HPA axis. Greater detailed analysis of these alterations may help discover new ways of treating stress pathologies including autoimmunities and depressive behaviors.