Serine protease inhibitors (Serpins) are involved in the regulation of various physiological processes common in all living organisms. In this review, we summarize recent published papers on insect serpins involved in the Toll signaling pathway, which produce antimicrobial peptides and regulate the prophenoloxidase (PPO) activation cascade which induces melanogenesis in model insects such as Drosophila melanoganster, Tenebrio molitor and Manduca sexta. In addition, we review research on serpins from entomopathogens, including viruses, nematodes, bacteria, fungi and parasitoids involved in the immuno-regulation of insect hosts.