Participation of the pineal gland and melatonin in the innate immune response is part of a dynamic and intricate network that acts throughout the inflammatory response, integrating signaling pathways and regulatory processes at the molecular, cellular and organism levels. The pineal gland is a target for pathogen-associated molecular patterns and for inflammatory mediators, and melatonin, which may be produced by the pineal gland or by activated immune-competent cells, plays a role in modulating inflammatory responses. Nocturnal melatonin surge is suppressed at the beginning of an inflammatory response in order to allow a full mounting of an innate immune response at any hour of the day. Melatonin produced at the site of a lesion by activated immune-competent cells favors phagocytosis and reduces inflammatory reactions that could promote tissue lesion. Here, we discuss the mechanism underneath this crosstalk between the pineal gland and the innate immune response and extend the concept of an Immune-Pineal Axis.