Arthropods have open circulatory systems and must seal wounds and keep bacteria from entering the hemocoel using efficient clotting systems. Enzymes that crosslink the clot include transglutaminase, which is phylogenetically conserved, and phenoloxidase, which is not found in vertebrates. Prophenoloxidase is usually activated through a proteolytic cascade similar to the vertebrate clotting cascade. The well-characterized clotting cascade in horseshoe crabs is strongly activated by bacterial elicitors, in contrast to vertebrate clotting where induction relies more on endogenous signals. Many arthropod clotting factors are not orthologues of blood clotting factors, but show novel architectures assembled from domains that are also found in their vertebrate counterparts. The cellular mechanisms that lead to coagulation of blood and hemolymph appear to be similar. Recent findings in Drosophila reveal parallels between developmental processes that involve epithelial fusion and wound healing, enabling genetic dissection of the signal pathways involved. This Review is the first in a series on interactions between haemostasis and inflammation.