beta 2-Glycoprotein I (beta 2-GPI), a plasma protein with in vitro anticoagulant properties, has been recognized to have an important role in the antiphospholipid syndrome (APS) as a cofactor and an (co)antigen in ELISA assays. Although beta 2-GPI levels were found to be increased in some patients with APS, the clinical value of measuring beta 2-GPI levels in APS is not known. Several reports have suggested that anti-beta 2-GPI antibodies may be a marker for the APS and might be more specific for the vascular complications of the APS than anticardiolipin antibodies. There have been major discoveries about phospholipid (PL) and antibody binding sites on beta 2-GPI, although more studies are needed. Reports of changes in cell membrane PL composition or exposure of other anionic molecules by apoptosis, cell activation and oxidative injury suggest mechanisms to explain beta 2-GPI binding and the generation of cryptic epitopes for aPL/anti-beta 2-GPI antibodies.