The complement system provides innate defense against microbial pathogens and is a “complement” to humoral (antibody-mediated) immunity. Consisting of plasma and membrane proteins, this proinflammatory system works in part by a cascade involving limited proteolysis whereby one component activates the next, resulting in a dramatic amplification. The overall goal is deposition of complement fragments on pathologic targets for the purposes of opsonization, lysis, and liberation of peptides that promote the inflammatory response. Deficiencies of complement components predispose to infections and autoimmune syndromes. Even though total deficiency of a complement component is rare, patients presenting with certain bacterial infections and autoimmune syndromes, especially SLE, have a much greater incidence of deficiency. This review will summarize the clinical manifestations and pathophysiology of congenital and acquired complement deficiency diseases. We will also present an algorithm for laboratory diagnosis of complement deficiency and discuss current and future therapeutic options.