The Innate Immune Response (IIR) is an evolutionarily derived process to protect cells and tissues from a broad spectrum of insults. Unfortunately abrogating the insult comes at a cost with compromise of cell or tissue integrity. For the CNS to function it needs to rigorously control its microenvironment and thus is highly susceptible to negative sequelae of the IIR. In the course of studying neuroinflammation in a wide variety of human CNS diseases, we discovered an intriguing molecule, CHI3L1, that appears to be crucial in mitigating untoward CNS effects of IIR. During neuroinflammation the distribution of CHI3L1 is completely unlike that in other tissues. In systemic tissues CHI3L1 is expressed highly in macrophages during the IIR, however in the CNS macrophage expression appears to be severely down-regulated and instead astrocytes express high levels. Experimental studies in animal models of CNS disease have suggested that CHI3L1 is part of a unique anti-inflammatory pathway in the CNS. The mechanism of CHI3L1 down-regulation in CNS macrophages and the role of astrocytic up-regulation remains to be elucidated, however this novel pathway offers a new target to regulate CNS inflammation.