Complement is an essential component of innate immunity and a major trigger of inflammatory responses. A critical step in complement activation is the formation of the C3 convertase of the alternative pathway (AP), a labile bimolecular complex formed by activated fragments of the C3 and factor B components that is fundamental to provide exponential amplification of the initial complement trigger. Regulation of the AP C3 convertase is essential to maintain complement homeostasis in plasma and to protect host cells and tissues from damage by complement. During the last decade, several studies have associated genetic variations in components and regulators of the AP C3 convertase with a number of chronic inflammatory diseases and susceptibility to infection. The functional characterization of these protein variants has helped to decipher the critical pathogenic mechanisms involved in some of these complement related disorders. In addition, these functional data together with recent 3D structures of the AP C3 convertase have provided fundamental insights into the assembly, activation and regulation of the AP C3 convertase.