It has become clear that β2-glycoprotein I (β2GPI) is the most common and best-characterised antigenic target for ‘antiphospholipid’ (aPL) autoantibodies. These antibodies preferentially bind β2GPI that has been immobilised on anionic phospholipid membranes or certain synthetic surfaces. These surfaces appear to act by increasing antigen density to allow binding of intrinsically low-affinity anti-β2GPI autoantibodies. Binding of β2GPI in fluid phase is weak and requires high concentrations of β2GPI. Our understanding of the pathophysiology of the ‘Antiphospholipid’ Syndrome (APS) has increased exponentially with the number of studies into the interactions of aPL antibodies and β2GPI.