Horseshoe crab hemocyte selectively responds to bacterial lipopolysaccharides(LPS), which depends critically on the proteolytic activity of the LPS-responsive serine protease zymogen factor C. In response to stimulation by LPS, the hemocyte secretes several kinds of immunocompetent proteins. The coagulation cascade triggered by LPS or β-1,3-D-glucans (BDG) results in the formation of coagulin fibrils that are subsequently stabilized by transglutaminase (TGase)-dependent cross-linking. Invading pathogens are recognized and agglutinated by lectins and then killed by antimicrobial peptides. Moreover, LPS-triggered hemocyte exocytosis is enhanced by a feedback mechanism in which the antimicrobial peptides serve as endogenous mediators. Factor C also acts as an LPS-sensitive complement C3 convertase. In addition, a sub-cuticular epidermis-derived protein forms a TGase-stabilized mesh at sites of injury. Horseshoe crabs have a sophisticated innate immune response network that coordinately effects pathogen recognition and killing, prophenoloxidase activation, complement activation and TGase-dependent wound healing.