Despite increasing knowledge of the immunology and pathophysiology of the antiphospholipid syndrome, treating this condition remains challenging. Because of a paucity of randomized controlled trials, many of the treatment recommendations are not evidence-based. Retrospective case series suggest that a high level of oral anticoagulation is needed to prevent recurrent thrombosis. The combination of heparin and low-dose aspirin is effective in significantly increasing the chances of a successful pregnancy in woman with recurrent pregnancy failure associated with antiphospholipid antibodies. Primary prevention with aspirin is justified in patients with antiphospholipid antibodies but without a prior history of thrombosis. Interesting and controversial issues in the treatment of the antiphospholipid syndrome include the use of less intensive anticoagulation or antiplatelet agents in some patient subsets, anticoagulation for certain nonstroke neurologic conditions, the role of other agents (hydroxychloroquine, antioxidants), and novel immunomodulatory strategies.