Initially defined as a defense against infection, the immune system is known to function in injury and repair and in age-related neurodegenerative diseases. Because of the capacity of immune cells to execute highly aggressive responses, precise control mechanisms are required to prevent collateral damage to healthy cells and to facilitate repair. PACAP is a neuropeptide that has evolved to function in these latter capacities and appears to do so at multiple levels. While PACAP is known to act directly on peripheral immune cells to modify their activities in vitro and to strongly modify inflammation and clinical symptomatology in rodent models of inflammatory diseases (see Chap. 7 ), considerable evidence indicates that PACAP is upregulated and acts within the compromised brain to regulate inflammatory and regenerative functions of astrocytes and microglia. Moreover, PACAP acts as a neurotransmitter/neuromodulator in the hypothalamus and peripheral nervous system and may thereby regulate inflammation in the periphery via its regulation of the hypothalamic pituitary adrenal axis (HPA) and autonomic control of immune cells in lymph nodes and other immune organs. While many details remain to be elucidated, we will describe in this chapter potential neural circuitries and mechanisms by which PACAP might regulate CNS and peripheral inflammation and immune cell function.