Patients with Hughes (antiphospholipid) syndrome who develop an initial thrombosis have an increased risk of subsequent thrombotic events. Current therapy to prevent recurrent thrombosis is controversial. While it seems clear that anticoagulant treatment is a better option than anti-aggregants alone, there is no consensus regarding the duration and intensity of oral anticoagulation. The risk of bleeding, the main complication of anticoagulant treatment, and the need for frequent monitoring of the International Normalized Ratio to measure the anticoagulant effect of warfarin concern patients and physicians. In addition, there is some debate about the validity of the International Normalized Ratio in patients with lupus anticoagulant activity. The development of new therapies that target more specific pathogenic mechanisms is highly warranted.