The immune system is deeply interconnected with the endogenous 24-h oscillators of the circadian system. Indeed, the connection between these two physiological systems occurs at multiple levels and in both directions. On one hand, various aspects of the immune system show daily rhythms, which appear to be essential for healthy immune maintenance and proper immune response. On the other hand, immune responses cause changes in circadian rhythms, disrupting their delicate balance and manifesting in disease. Indeed, immune challenges cause various time-, gene-, and tissue-specific effects on circadian-regulated factors. This article reviews the possible mediators of the cross talk between the circadian clock and the immune system, in particular the inflammatory pathways. The rhythmic expression of cytokines and their receptors, as well as other rhythmically regulated humoral factors such as glucocorticoids, melatonin, leptin, or prostaglandins, could gate the effects of the immune response on the circadian system. In addition, systemic cues such as body temperature and neuronal connections between the brain and peripheral tissues may underlie the immune-circadian communication.