The complement system is a vital component of the host immune system, but when dysregulated, can also cause disease. The system is activated by three pathways: classical, lectin and alternative. The initiating proteases of the classical and lectin pathways have similar domain structure and employ similar mechanisms of activation. The C1r, C1s and MASP-2 proteases have the most defined roles in the activation of the system. This review focuses on the mechanisms whereby their interaction with substrates and inhibitors is regulated.