Mannose-binding lectin (MBL) is a serum component which participates in innate immunity by activating complement via a novel pathway. Human MBL forms complexes with two types of serine proteases termed MASP (MBL-associated serine protease). These two proteases, MASP1 and MASP2, are structurally similar to one another as well as to C1r and C1s. Together, MASP, C1r and C1s constitute a novel serine protease family. It is likely that human MASP1 is able to activate C3, while human MASP2 cleaves C4, although further functional studies are required to confirm this. Based on the analysis of MASP cDNA of vertebrates and ascidians, the MASP/C1r/C1s family can be classified into two groups. The first group is characterized by a histidine loop in its serine protease domain, an active-center serine encoded by TCN, and a proline as the amino acid residue at the-3 position from the active serine. Human MASP1, mouse MASP1, Xenopus MASP1 and ascidian MASPs all belong to this group. MASP of the second group has structural features which are distinct from those of the first group: an absence of a histidine loop, an active-serine encoded by AGY, and an alanine or valine as the amino acid residue at the -3 position from the active-serine. The second group includes human MASP2, Xenopus MASP2, carp MASP, shark MASP, C1r and C1s. The TCN-type of MASP may have emerged prior to the AGY-type as an ancestral protease of the MASP/C1r/C1s family and played a crucial role in cleaving C3.