The aim of this report was an overview of beta2-glycoprotein I (beta2-GPI)- and annexin A5 (AnxA5)-phospholipid interactions including candidate beta2-GPI receptors, and their relevance to the investigation of physiological/pathological processes. Both beta2-GPI and AnxA5 have thrombomodulatory functions in vivo and their antigenicity is particularly important for thrombotic manifestations and pregnancy complications in antiphospholipid syndrome. Specific elements of beta2-GPI- and AnxA5-phospholipid interactions are different. The crucial elements for beta2-GPI are conformational change and dimerization, both of which are also required and necessary for receptor signaling, leading to the prothombotic state. AnxA5 differs in its ability to crystallize into a protective shield, the disruption of which seems to be the major prothrombotic mechanism. These differences may explain some of the functional consequences of both molecules seen in the pathological conditions. Future alternative therapies of antiphospholipid syndrome are proposed to be based on the expanding knowledge of beta2-GPI- and AnxA5-phospholipid interactions, specifically antagonizing beta2-GPI receptors, as well as inhibiting their signaling pathways.