This chapter focuses on the association between acquired and inherited thrombophilia and implantation failure (IF). The pathogenesis of recurrent IF in patients with thrombophilic gene mutation may involve the effect of hypofibrinolysis on trophoblast migration. Trophoblastic migration and invasion during implantation involve extracellular matrix degradation, which is facilitated by matrix metalloproteinases (MMP). Recently, a variety of pathogenetic mechanisms have been suggested to explain the prothrombotic effect of antiphospholipid antibody (APA), the main cause of acquired thrombophilia. Recently, it has been suggested that APA may negatively impact the transformation of the endometrium into decidua, creating a hostile environment for blastocyst implantation. The chapter investigates the main therapeutic modalities such as heparin, aspirin (ASA), corticosteroids, and intravenous immunoglobulin alone or in combinations for treatment of IF. It is premature to recommend anticoagulation for patients with thrombophilia and IF.