This review focuses on the powerful pain facilitatory effects produced by the immune system. Immune cells, activated in response to infection, inflammation, or trauma, release proteins called proinflammatory cytokines. These proinflammatory cytokines signal the central nervous system, thereby creating exaggerated pain as well as an entire constellation of physiological, behavioral, and hormonal changes. These changes are collectively referred to as the sickness response. Release of proinflammatory cytokines by immune cells in the body leads, in turn, to release of proinflammatory cytokines by glia within the brain and spinal cord. Evidence is reviewed supporting the idea that proinflammatory cytokines exert powerful pain facilitatory effects following their release in the body, in the brain, and in the spinal cord. Such exaggerated pain states naturally occur in situations involving infection, inflammation, or trauma of the skin, of peripheral nerves, and of the central nervous system itself. Implications for human pain conditions are discussed.