Microbial infection poses a threat to organismal homeostasis and therefore must be efficiently counteracted by host defense mechanisms. It has been recently demonstrated that the immune system may anticipate an emerging pathogenic exposure through a heightened inflammatory state. Such anticipatory responses to fluctuating environmental conditions are typically orchestrated by the circadian clock, an intrinsic time-keeping system that adapts tissue physiology to diurnal variations in external influences. Here, we review current knowledge about the interplay between the circadian clock and antimicrobial responses. We summarize the molecular strategies employed by the circadian system against specific pathogens, the core-clock proteins as well as cells in which they are expressed that mediate host defense, and the consequences of circadian variations on immune function. Furthermore, we highlight the possible implications of such circadian gating in immune reactions against pathogenic infections for the chronopharmacology of antibacterial and antiviral therapies.