Sensory nerves are abundant in lymphoid organs and rapidly release the neuropeptide calcitonin gene-related peptide (CGRP) in response to injury or infection. CGRP directly acts on macrophages and dendritic cells and inhibits the capacity of these cells to produce inflammatory cytokines and to present antigens to T cells. Effector mechanisms, by which CGRP acts on innate immune cells, include upregulation of IL-10, IL-10-independent induction of the inducible cAMP early repressor (ICER) and inhibition of NF-κB activity. Engagement of the CGRP receptor, which is composed of receptor activity modifying protein-1 (RAMP1) and calcitonin receptor-like receptor (CLR), increases cellular cAMP levels leading to the activation of protein kinase A (PKA). PKA appears crucial for mediating the antiinflammatory effects of CGRP. Available evidence therefore indicates that CGRP acts as a negative regulator of innate immune responses and contributes to limiting tissue damage in inflammatory disorders. In sepsis caused by mixed-bacterial infection, however, antiinflammatory activities of CGRP may exaggerate leading to immunosuppression and impaired host defense.