The antiphospholipid syndrome (APS) is the most common acquired thrombophilia. It is characterized by venous and arterial thrombosis, recurrent pregnancy loss, and various other clinical manifestations in the presence of antiphospholipid antibodies (aPL). Like other autoimmune diseases, the etiology of APS derives from a combination of genetic and environmental factors. The most significant environmental factors in APS are infectious agents, followed by trauma and drugs. Infections can induce aPL and, in the catastrophic variant of APS, about one-third of cases are associated with a clear recent infection. On their formation, aPL have been clearly shown to be pathogenic, because they influence all arms of the coagulation system and because passive transfer and active immunization protocols have demonstrated. Therefore, in a genetically susceptible individual, exposure to one or more infectious agent can cause a molecular mimicry and result in the production of pathogenic aPL that can induce thrombosis and pregnancy loss. Identification of the epitopes within the beta-2-glycoprotein-I molecule that serves as the target for autoantibodies makes them the target for immunomodulation of the syndrome.