α₂‐macroglobulin (α₂M) and related proteins share the function of binding host or foreign peptides and particles, thereby serving as humoral defense barriers against pathogens in the plasma and tissues of vertebrates. In human α₂M, several reactive sites including high‐affinity sites for zinc, transglutaminase cross‐linking sites, and reactive sites derived from the activated thiol ester can mediate reversible or irreversible capture of proteins of diverse biological functions. α₂M interacts and captures virtually any proteinase whether self or foreign, suggesting a function as a unique “panproteinase inhibitor.” Activation of α₂M generates novel binding sites, which mediate complex formation with cytokines and other peptides. Direct evidence of physical association of cytokines with activated α₂M indicated its role as biological response modifier in cell cultures. A mechanism commonly referred to as “clearance of activated α₂M” involves C a²⁺‐dependent binding to a specific cell surface receptor, a member of the low‐density lipoprotein receptor supergene family, that mediates cellular uptake by endocytosis and delivery to endosomes and lysosomes. The peptide binding function of α₂M, therefore, may also be viewed as a mechanism that allows targeting of biologically active peptides to different cell types expressing the α₂M receptor. Internalized complexes may be dispatched into different pathways of endocytic/lysosomal pathways in a cell type‐specific manner. In addition, bioactive peptides bound to α₂M may dissociate in the process of intracellular ligand sorting, thereby modulating cell function, or remain bound and share the catabolic fate of α₂M. The diversified and probably programmed binding functions of α₂M indicate that in addition to its role in trapping proteinases, it has other biological activities that remain to be fully defined. That α₂M may function as a binding and carrier protein with targeting characteristics is predicted from 1) the known functions of α₂M, and 2) the similarity of the fate of α₂M with proteins whose significance in targeting and intracellular trafficking has been studied in more detail.— Borth, W. α₂‐Macroglobulin, a multifunctional binding protein with targeting characteristics. FASEB J. 6: 3345‐3353; 1992.