Histidine-rich glycoprotein (HRG) is plasma glycoprotein that has a multidomain structure, interacts with many ligands, and exhibit many modulatory functions in diverse biological systems. HRG ligands include Zn2+, tropomyosin, heparin and heparan sulphate, plasminogen, plasmin, fibrinogen, thrombospondin, IgG, FcgR, and complement. In many cases, the histidine-rich region of the molecule enhances ligand binding after interaction with Zn2+ or exposure to low pH, conditions associated with sites of tissue injury or tumor growth. The multidomain nature of HRG and diverse ligand binding properties indicates that it can act as an extracellular adaptor protein, bridging together different ligands mainly on cell surfaces. Apart from cell surface molecules, HRG can differentially target IgG, preventing generation of insoluble immune complexes. HRG binds to most cells primarily via heparan sulphate proteoglycans. HRG can enhance clearance of apoptotic and necrotic phagocytes as well as immune complexes. The anti-angiogenic properties of HRG are well established in vitro and in vivo. HRG can modulate other physiological processes such as cell adhesion and migration, fibrinolysis and coagulation, complement activation. This review presents an update on the molecular, structural, biological, and clinical properties of HRG and associated autoimmunity conditions.