A large body of evidence suggests that neuroinflammation lies at the core of nearly all CNS disorders, including psychiatric disorders. Invading and local immune cells orchestrate the series of events that lead to either tissue repair or damage in response to neuroinflammation. Both lymphocytes and microglia express metabotropic glutamate (mGlu) receptors, which respond to glutamate or other endogenous activators (e.g. some kynurenine metabolites of tryptophan metabolism) influencing immune phenotype and the balance between pro-inflammatory and anti-inflammatory cytokines. Here, we offer an up-to-date on the role of individual mGlu receptor subtypes in the regulation of innate and adaptive immune response, highlighting the relevance of this information in the development of subtype-selective mGlu receptor ligands for treatment of CNS disorders.