Publisher Summary This chapter emphasizes the potential applications of studies of complement biosynthesis and presents a review of the historical aspects of work on this problem. The methods for studies of complement synthesis include tissue culture conditions (media and cells), assay systems, biosynthesis in vivo, and a criteria for establishing that a given cell or tissue is a site of synthesis of a complement protein. The sites of synthesis of the individual complement proteins are described based on the biosynthesis of C1, C2, C4, C3, C5 and C6, C7, C8, C9, and complement–associated proteins. The approaches to study fetal synthesis of complement are (1) synthesis of specific complement components in vitro by isolated fetal tissues; (2) demonstration of a maternal-fetal discordance of genetic type in those complement proteins exhibiting genetic polymorphisms; and (3) a method showing the presence of a complement component in sera of fetuses borne by genetically deficient mothers. Most of the complement proteins are synthesized early in fetal life, and in several species (man, rodents, and ungulates) the placenta is an effective barrier to passage of complement either from or to the fetal circulation. The chapter describes the genetically determined complement deficiencies such as C4 deficiency, C5 deficiency, C2 deficiency, and deficiency of C1 inhibitor in man and experimental animals. The advantage of using complement as a model system for genetic studies is the ease of detecting the gene product, the large number of well-characterized genetic abnormalities, and the availability of cell lines capable of synthesizing individual complement proteins. Finally, the chapter discusses the nongenetic control of complement biosynthesis.