Sleep-immune interactions are well-known phenomena in everyday life and folk wisdom. There is no doubt that an infection makes us tired and increases the desire to sleep, and a good night’s sleep is commonly recommended as “the best medicine” for an infectious disease. Along this line, it is assumed that prolonged sleep loss weakens our body’s defense system and thus renders us more prone to catch a cold or any other infection. The scientific analyses of these notions started in 350 BC, when Artistotle elaborated in his book On Sleep and Sleeplessness that sleep is induced by hot vapors that arise from the stomach during digestion, and that a similar sleep response can be observed in feverish patients (16). In the early 20th century, researchers postulated a hypnotoxin that increases during wakefulness, induces sleep, and is cleared again during sleep (265, 333). The first hypnotoxin, discovered in the 1980s, turned out to be the bacterial cell wall component muramyl peptide, and like more than 2,000 yr ago, it was assumed that it derives from the gastrointestinal tract (304). By activating the immune system and the release of sleep regulatory substances like the cytokines tumor necrosis factor (TNF) and interleukin (IL)-1, these muramyl peptides and other microbial products were shown in animal models to contribute to the homeostatic regulation of slow-wave sleep (SWS), the deepest form of sleep. We now know that both cytokines likewise mediate the SWS response to an infectious challenge (353). With respect to the sleep-to-immune directionality, early studies in the late 19th century showed that total sleep deprivation in dogs leads to death after several days (reviewed in Ref. 38). Later studies using more controlled approaches found that sleep deprivation of rats is lethal after~ 2–3 wk (459), and a breakdown of host defense indicated by a systemic bacterial infection was reported after applying the same method of sleep deprivation (172, 175). Together with other experiments from recent times, these findings suggest an important role of sleep for immune defense (47, 79).