Various antigen structures initiate the classical and the lectin pathways of complement activation. Multidomain modular proteases (C1r, C1s and MASPs) are involved in the initiation complexes of both pathways. Despite the identical domain organization of these serine proteases there are differences in their specificities and functions. A comparative analysis is given on the similarities and differences of the mechanism of action of these proteases, with emphasize on structural aspects. Recent structural and functional data underline the significance of molecular dynamics in the activation process of both C1 and MBL/MASPs. While the role of MASP-2 in the lectin pathway is supported by increasing number of evidence, the same can not be said about MASP-1 and MASP-3. The role of the initiation complexes in pathological processes such as inflammation and subsequent repair processes, apoptosis, susceptibility to infectious diseases etc. is also reviewed. C1 inhibitor is essential in regulating both pathways. This serpin interacts with several serine proteases including C1r, C1s and MASPs. C1 inhibitor deficiency related diseases, and C1 inhibitor as a therapeutic agent is also discussed.