Personal experience indicates we sleep differently when sick. Data reviewed demonstrate the extent to which sleep is altered during the course of infection of host organisms by several classes of pathogens. One important unanswered question is whether or not the alterations in sleep during infection are of functional relevance. That is, does the way we sleep when sick facilitate or impede recovery? One retrospective, preclinical study suggests that sleep changes during infection are of functional relevance. Toth and colleagues [102] analyzed sleep responses of rabbits to three different microbial infections. Those rabbits that exhibited robust increases in NREM sleep were more likely to survive than those that exhibited long periods of NREM sleep suppression. These tantalizing data suggest that the precise alterations in sleep through the course of infection are important determinants of morbidity and mortality. Data from healthy subjects demonstrate a role for at least two cytokines in the regulation of spontaneous, physiologic NREM sleep. A second critical yet unanswered question is whether or not cytokines mediate infection-induced alterations in sleep. The hypothesis that cytokines mediate infection-induced alterations in sleep is logical based on observations of the impact of infection on levels of cytokines in the peripheral immune system and in the brain. No attempts have been made to intervene with cytokine systems in brain during the course of infection to determine if there is an impact on infection-induced alterations in sleep. Although substantial progress has been made in elucidating the myriad mechanisms by which cytokines regulate and modulate sleep, much remains to be determined with respect to mechanistic and functional aspects of infection-induced alterations in sleep.