The third complement component (C3) is a multifunctional glycoprotein that interacts with numerous serum proteins, cell surface receptors, and membrane-associated regulatory proteins. Deficiencies of C3 have been reported in several human kindred of different ethnic backgrounds and from different geographic regions. In addition, inherited C3 deficiency has been discovered in certain strains of guinea pigs, dogs, and rabbits, and has been experimentally induced in animals by injections of cobra venom factor. Studies of the C3-deficient humans and animals have demonstrated the important roles performed by C3 in the immune response, opsonization and phagocytosis of pathogens, and immune complex solubilization. Current knowledge of the molecular and cellular basis of complement C3 deficiency indicates that C3 deficiency is caused by numerous molecular genetic mutations that include splicing defects, a partial gene deletion, and a critical amino acid substitution. With the advent of gene ablation technology, C3-deficient murine models can now be established, making it possible to examine the role that C3 plays in the molecular pathogenesis of many different diseases.