Antibodies against phospholipids and phospholipid-binding proteins, especially anti-cardiolipin and anti-beta2-glycoprotein I antibodies, are important diagnostic markers of autoimmune thrombophilia. These autoantibodies are quite common among patients with systemic lupus erythematosus but can also be found in individuals without concurrent rheumatic conditions. Apart from thromboembolic disease, these antibodies are linked to recurring fetal loss and intrauterine fetal death. In patients with recurring thrombotic events in whom anti-phospholipid antibodies or prolonged aPTT (as a sign of lupus anticoagulant activity) is found, long-term or even lifelong anticoagulation therapy should be considered. Habitual spontaneous abortions and other obstetric complications are often preventable with LMW heparin in combination with low-dose acetylsalicylic acid. In this review, we outline a diagnostic strategy for uncovering autoimmune thrombophilia supplemented with functional and genetic tests for hypercoagulability.