Melanization is a unique defence mechanism in arthropods involved in wound healing and pathogen encapsulation. Phenoloxidases (PPOs) are key enzymes of melanization, which mediate the enzymatic conversion of tyrosine to eumelanin. A serine-protease (SP) cascade, similar to the blood-clotting cascade of vertebrates, proteolytically activates prophenoloxidases to phenoloxidases. This proteolytic activation is tightly controlled by serpins and other melanization inhibitors. Melanization has been regarded as one of key immune responses against malaria parasites in mosquitoes. The ookinete melanization of both the simian malaria parasite, Plasmodium cynomolgi, and of the rodent parasite, Plasmodium berghei, prevent parasite development in the human malaria vector, An, gambiae. However, the recent studies revealed a melanization response regulated by Serpin-2 and two C-type lectins (CTL4 and CTLMA-2) was shown to result in ookinete melanization but did not affect the development of the natural human parasite P. falciparum in the mosquito. Instead of melanization, TEP1/APL1/LRIM1 complement-like pathway has been identified as major immune response that regulate parasite loads in the natural association of An. gambiae and P. falciparum. The studies by me and my colleagues revealed another melanization response independent on Serpin-2. Genome analyses of mosquitoes revealed a large expansion of the PPO, SP, and serpin genes potentially involved in the melanization pathway. This expansion was devoted to existence of at least two distinct SP-Serpin regulation modules in controlling separate melanization responses, tissue and hemolymph melanization, in the mosquito, Aedes aegypti. Tissue melanization regulated by Serpin-2 has role in melanotic tumor formation, but not in ookinete melanization. Hemolymph melanization regulated by Serpin-1 and a couple of SPs was activated by the infection of various pathogens and is involved in anti-malarial defense against the avian malaria parasite, P. gallinaceum. A new type of regulator, CLSP2, negatively modulate this hemolymph melanization. Cross-talk between hemolymph melanization and complement-like pathway will be discussed.