Monoclonal antiphospholipid antibodies (aPL) have been utilized to dissect the relationship between their sequence, structure, binding and biological properties relevant to the pathogenesis of the antiphospholipid syndrome. In particular, sequence analysis of aPL has highlighted the clustering of certain amino acid residues in the antigen contact sites of their heavy and light chains. Therefore, these sequence motifs are likely to be important in determining aPL binding properties and their pathogenic effects. Experiments, however, using monoclonal aPL engineered to contain specific point mutations in their sequence which alter their ability to bind relevant antigens have shown that these alterations in binding are not directly mirrored by their pathogenic effects. In this review we focus on work carried out by others and ourselves using monoclonal antibodies with specific binding properties to extend our knowledge of the non-linear structure-binding-function relationship of aPL.