In humans, S100A12 (also named Calgranulin C and EN-RAGE) is mainly expressed and secreted by neutrophil granulocytes. Extracellular S100A12 is involved in innate immune responses against microorganisms and parasites. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), which is a cell surface receptor on macrophages, endothelium, and lymphocytes. In a recent study, Realegeno et al. showed that S100A12 exerts antimicrobial activity against Mycobacterium leprae in infected human macrophages. Recently, some interesting data on the antimicrobial activity of S100A12 have been reported. Proinflammatory role of S100A12 is supported by another newly found receptor, Toll-like receptor 4 (TLR4). These observations emphasize the importance of S100A12 for the development of potential therapeutic approaches to increase protective immunity or reduce immunopathogenesis.