Many immune parameters show systematic fluctuations over the 24-h day in human blood. Circulating naive T-cells and production of proinflammatory cytokines, like interleukin-12 (IL-12), peak during nighttime, whereas cytotoxic effector leukocytes and production of the anti-inflammatory cytokine IL-10 peak during daytime. These temporal changes originate from a combined influence of the circadian system and sleep. Both brain functions act synergistically and share neuroendocrine effector mechanisms to convey control over immune functions. Sympathetic tone and cortisol levels show a circadian nadir during nighttime and are further suppressed by sleep, whereas growth hormone and prolactin show a circadian peak during nighttime and are further enhanced by sleep. Thus, the circadian system and sleep jointly evoke a unique endocrine constellation that is extremely effective in inducing changes in leukocyte traffic and a shift toward proinflammatory type 1-cytokines during the nocturnal period of sleep, that is, an action with strong clinical implications.