Innate immunity is essential for the wellbeing of vertebrates and invertebrates.Key components of this defense system include patte recognition receptors that bind to infectious agents, extra-and intra-cellular proteins that relay signals, as well as molecules and cells that eliminate pathogens. We have been studying the defense mechanisms in a biochemical model insect, Manduca sexta. In this insect, hemolin, peptidoglycan recognition proteins, β-1,3-glucan recognition proteins and C-type lectins detect microbial surface molecules and induce immune responses such as phagocytosis, nodulation, encapsulation,melanization and production of antimicrobial peptides. Some of these responses are mediated by extracellular serine proteinase pathways. The proteolytic activation of prophenoloxidase (proPO) yields active phenoloxidase (PO) which catalyzes the formation of quinones and melanin for wound healing and microbe killing. M. sexta hemolymph proteinase 14 (HP 14) precursor interacts with peptidoglycan or β- 1,3-glucan, autoactivates,and leads to the activation of other HPs including HP21 and proPO-activating proteinases (PAPs). PAP-1, -2 and -3 cut proPO to generate active PO in the presence of two serine proteinase homologs. Inhibition of the proteinases by serpins and association of the proteinase homologs with bacteria ensure a localized defense reaction. M. sexta HP1, HP6,HP8, HP17 and other proteinases may also participate in proPO activation or processing of sp(a)tzle and plasmatocyte spreading peptide.