Anticoagulation with oral vitamin K antagonists (VKA) is the mainstay of the treatment of venous and/or arterial thromboembolism in patients with antiphospholipid syndrome (APS), although the optimal intensity of anticoagulation remains controversial. The limitations of existing anticoagulants have driven a search for novel agents. Dabigatran etexilate (Pradaxa), a direct thrombin inhibitor (DTI), and rivaroxaban (Xarelto), the first in a new class of drugs, the oral direct factor Xa (FXa) inhibitors, are both fixed-dose orally administered agents. They are now licensed in the UK and Europe for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective total hip replacement (THR) or total knee replacement (TKR). Prospective randomized clinical trials suggest that these agents, and also apixaban, a further oral direct anti-Xa inhibitor, may have potential in other areas including the treatment of acute VTE, prevention of stroke or systemic embolism in patients with atrial fibrillation (AF) and acute coronary syndromes. Here, we summarize current indications for these agents and address the potential for their use in patients with thrombotic APS.