Inter-alpha-trypsin inhibitor family proteins are mainly detected in plasma and urine and comprise the common light chain bikunin and at least 6 closely related heavy chains. The bikunin moiety exhibits protease inhibitory activity and has been studied extensively; however, the heavy chains have been largely overlooked. Recent studies clearly indicate that the heavy chain moieties have important biological functions either in association with or independent of bikunin. Because the heavy chains comprise the main part of the protein structure of this family, it is important to understand their functions. This review summarizes the domain structural features of heavy chains, the heavy chain-interacting molecules identified thus far, and the association of heavy chains with diseases to encourage the discovery of novel heavy chains-interacting molecules and to gain a deeper insight into their functions.