Publisher Summary This chapter describes experiments that utilize genetic structural variants or deficiency states in the study of complement function in general. It also discusses the clinical aspects of hereditary angioneurotic edema and its pathogenesis. It also presents the characteristics of the defect and applications of the model in guinea pigs deficient in the “third component of complement,” C5 deficiency in mice, C5 dysfunction in man, and C6 deficiency in rabbits. Structural genetic polymorphisms aid the investigation of structure-function relationships in the complement system. Such polymorphisms may also provide hints about the structure of the complement proteins themselves. From an immunological and complementological point of view, the most important aspect of genetic variation in the complement system has been and will be the use of inherited deficiency and dysfunctional states in defining the role of complement in reactions that play a role in host defense against infection and injury. In this sense, these “natural experiments” provides with superb controls for in vitro systems and the schemata derived there from.