Abstract The multifunctional nature of mast cells (MCs) has been revealed through their involvement in both innate and adaptive immune responses. Recent insight into the various functions of MCs has shown that these innate immune effectors possess the dual ability to kill microbes and to modify classical adaptive immune responses. Members of the cathelicidin family of antimicrobial peptides (AMPs) are expressed by MCs and epithelial cells at sites of injury. The granular localization of the cathelicidin peptides, their extracellular release, and their capacity to modify inflammatory responses suggests that cathelicidin plays an important role in the capacity of MCs to combat skin infection. Preliminary data inside this proposal show that MCs are sentinels in the skin for defending against bacterial and viral infections. Mast cell-deficient (KitW-sash-/-) mice are more susceptible to skin infection than the wild-type mice, while KitW-sash-/- mice reconstituted with skin MCs show a normal response. Using MCs derived from mice deficient in cathelicidin, we showed that antimicrobial peptides (AMPs) are critical anti- pathogenic granule components. Signaling through toll-like receptor (TLR)-2 increased the level of antimicrobial peptide MCs, enhancing their capacity to fight skin infections. The central hypothesis of this proposal is that MCs play a seminal role in the skin innate immune response to infections by orchestrating other cell responses and expressing cathelicidin peptides. Several of the experiments will focus on establishing how MCs modify skin microenvironment and coordinate with other cells to respond to infection (Aim 1). Once the contribution of MCs in skin innate immune defense has been elucidated, Aim 2 will examine the regulation and function of MC AMPs during skin infections. Understanding the role of MCs in skin defense against foreign pathogens will suggest new therapeutic targets for combating infection.