Personal experience and empirical data indicate sleep is altered during sickness. Important signaling molecules of the peripheral immune system called cytokines orchestrate responses to infection. Through a variety of mechanisms, the brain detects activation of the peripheral immune system. The brain responds to infection by altering physiological processes and complex behavior, including sleep. These changes in physiology and behavior collectively function to support the immune system, and under normal circumstances the health of the host is restored. Several of these cytokines, and their receptors, are present in normal healthy brain. Some cytokines regulate sleep under physiological conditions, in the absence of infection or immune challenge. For example, interleukin-1 directly alters discharge patterns of neurons in hypothalamic and brainstem circuits implicated in the regulation of sleep-wake behavior. Many other cytokines modulate sleep because they interact with neurotransmitter, peptide, and/or hormone systems to initiate a cascade of responses that subsequently alter sleep-wake behavior. Because cytokines regulate/modulate sleep-wake behavior in the absence of immune challenge, and cytokine concentrations and profiles are altered during infection, it is likely that cytokines mediate infection-induced alterations in sleep. Whether the changes in sleep that occur during infection are beneficial and aid in recovery remains to be determined.