Horseshoe crab haemolymph contains a single type of cells, granular haemocytes, which are extremely sensitive to bacterial lipopolysaccharides (LPS) and lead to haemolymph coagulation. Sadaaki Iwanaga isolated protease zymogens from the haemocytes and reconstituted LPS and beta-1,3-d-glucans-mediated haemolymph coagulation. This led to the first discovery of a proteolytic cascade triggered by pathogen-associated molecular patterns, an important milestone for studies on invertebrate innate immunity. Moreover, he separated components derived from haemocyte granules and haemolymph plasma, and consequently identified unique defense molecules, such as lectins, serpins, cystatins, antimicrobial substances and substrates for transglutaminase. Through steady and persistent studies on the horseshoe crab host defense system, he made great progress in the field. Now we know that LPS-induced haemocyte exocytosis leads not only to coagulation but also activates a sophisticated immune response network that coordinately induces pathogen recognition, elimination and wound healing.