Three major interactions of the regulators of complement activation (RCA) proteins have been described: decay acceleration hastens the dissociation of the C3 convertases that produce the C3b molecules; cofactor activity irreversibly inhibits C3b and C4b effects through I-mediated proteolysis of target-bound and fluid-phase C3b and C4b; and C3b and C4b receptors are involved in the binding, transport, and clearance of foreign material in the spleen and liver, the mediation of endocytosis, and in signal transduction. The RCA proteins play major roles in the protection of cells from complement in regulation of complement activation, in processing of immune complexes, microbes, and other foreign materials, and in the activation of the immune cells. Two distinct biochemical mechanisms are instrumental in this process of biochemical interactions of the RCA proteins with C3b/C4b: decay acceleration and factor I-mediated degradation. It was not apparent that the RCA proteins were closely related when they were first being isolated and characterized. Factor H and C4bp were very different in molecular weight and each had its own ligand specificity, while the receptor, CR1, had not yet appeared structurally similar to either plasma protein. The use of pulsed-field gel electrophoresis has recently given the first detailed picture of the RCA cluster. The study of the RCA proteins has been accelerated by the availability of molecular techniques. This chapter discusses the physiological roles of the RCA family stress; the common structural and evolutionary relationships among the RCA proteins and their genes.