Sickness behavior refers to the coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the effects of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα), in the brain. Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the body site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism's priorities to cope with infectious pathogens. There is clinical and experimental evidence that activation of the brain cytokine system is associated with depression, although the exact relationship between sickness behavior and depression is still elusive.