Anti-phospholipid antibodies (aPLs) are present in a wide range of infectious and autoimmune diseases. aPLs, in particular anti-cardiolipin antibodies (aCL) and lupus anticoagulants (LA), are of considerable clinical importance because of the close association with predominant clinical features of venous, arterial thrombosis, and pregnancy morbidity. The term "antiphospholipid syndrome (APS)" has been used to define this set of pathologic features. Numerous studies have elucidated the specificity of anti-phospholipid antibodies (aPLs). It is clear that the nomenclature of aPLs is a misnomer and that these autoantibodies react with phospholipid-binding plasma proteins (cofactors), such as β2-glycoprotein, prothrombin, annexin V, high-molecular-weight kininogen, protein S, and protein C. Many varieties of pathophysiologic mechanisms have been explored in order to understand the wide spectrum of antigenic specificities of aPLs. Numerous observations are reviewed in this discussion concerning putative mechanisms related to anti-β2-GPI antibodies or other aPLs predisposing to thrombosis and to atherosclerosis. © 2004 Elsevier Inc. All rights reserved.