Autoantibodies directed to phospholipids or to phospholipid binding proteins are now studied using a growing number of laboratory tests. However, the history of the interest in this area goes back to the identification of the so-called false positive reactions in the non-treponemal serological test for syphilis (STS) and to the subsequent description of an in vitro coagulation defect called lupus anticoagulant (LAC). In the 1980s the introduction of the anticardiolipin antibody (aCL) immunoassay was a determining factor in the definition of the antiphospholipid syndrome (APS). In addition, lupus prone mice spontaneously producing aCL antibodies and normal mice passively infused with these antibodies provided useful models for the study of the pathogenic role of aPL. When in 1990 a phospholipid binding protein (beta 2glycoprotein I, beta 2GPI) was identified as the cofactor required for aCL antibody binding, the true antigenic target of the antibodies was first discussed. Soon afterwards an anti-beta 2GPI ELISA was developed that has proved to be of great clinical significance. We will discuss here the similarities and differences between these various assays (LAC, aCL, and anti-beta 2GPI), focusing on their specificity, sensitivity and practical applications.