Antiphospholipid antibodies (aPL) are a family of autoantibodies directed against phospholipid-binding plasma proteins, most commonly beta(2)-glycoprotein-I. Primary thrombosis prevention in persistently aPL-positive individuals requires a risk-stratified approach; elimination of reversible thrombosis risk factors and aggressive prophylaxis during high-risk periods are crucial. The effectiveness of aspirin in persistently aPL-positive patients without vascular involvement is not supported by data from prospective, controlled studies. For the secondary prevention of thrombosis in persistently aPL-positive individuals, the current recommendation is life-long warfarin; however, determining the intensity and duration of warfarin treatment, as well as the role of alternative anticoagulants, requires further research. The effectiveness of high-intensity anticoagulation in patients with antiphospholipid syndrome (APS) and vascular involvement is not supported by data from prospective, controlled studies. Patients with catastrophic APS usually receive a combination of anticoagulants, corticosteroids, intravenous immunoglobulin and plasma exchange; however, despite this aggressive approach, the mortality rate remains high. Potential new approaches for the management of persistently aPL-positive patients include hydroxychloroquine, statins, rituximab, complement inhibition, and other targeted therapies that have been effective in experimental APS models.