Annexin A2 is a multicompartmental protein that orchestrates a spectrum of dynamic membrane-related events. At cell surfaces, A2 forms the (A2•S100A10)2 complex which accelerates tissue plasminogen activator-dependent activation of the fibrinolytic protease, plasmin. Anti-A2 antibodies are associated with clinical thrombosis in antiphospholipid syndrome, whereas overexpression of A2 promotes hyperfibrinolytic bleeding in acute promyelocytic leukemia. A2 is upregulated in hypoxic tissues, and mice deficient in A2 are resistant to hypoxia-related retinal neovascularization in a model of diabetic retinopathy. Within the cell, A2 regulates membrane fusion processes involved in the secretion of pre-packaged, ultra-large molecules. In stimulated dendritic cells, A2 maintains lysosomal membrane integrity, thereby modulating inflammasome activation and cytokine secretion. Together, these findings suggest an emerging, multifaceted role for annexin A2 in human health and disease. The author's work has been inspired by numerous colleagues and mentors, and by the author's grandfather, and former ACCA member, Dr. J. Burns Amberson.