Antiphospholipid antibodies (aPL) may accompany a response to many infectious agents. The emergence of aPL may be transient or associated with the clinical picture of antiphospholipid syndrome (APS) with thrombosis, recurrent foetal loss, central nervous system, and other organ involvement. The most studied pathogenic aPL antibodies are directed to the β2-glycoprotein-I (β2GPI) molecule. Studies on experimental APS models proved that molecular mimicry between β2GPI-related synthetic peptides and structures within bacteria, viruses, and tetanus toxoid can induce experimental APS. Any explanation of how microbial infections might trigger APS must take into account the observation that all individuals appear to harbour potentially autoreactive lymphocytes, as well as natural aPL, but they remain innocuous unless somehow activated by a second hit. In this chapter, we discuss the association of aPL with infections, vaccines, and drugs, with molecular mimicry as a proposed cause for the development of APS.