Annexins are cytosolic proteins with conserved three-dimensional structures that bind acidic phospholipids in cellular membranes at elevated Ca2+ levels. Through this they act as Ca2+-regulated membrane binding modules that organize membrane lipids, facilitating cellular membrane transport but also displaying extracellular activities. Recent discoveries highlight annexins as sensors and regulators of cellular and organismal stress, controlling inflammatory reactions in mammals, environmental stress in plants, and cellular responses to plasma membrane rupture. Here, we describe the role of annexins as Ca2+-regulated membrane binding modules that sense and respond to cellular stress and share our view on future research directions in the field.Work in our laboratories was supported by grants from the German Research Foundation to V.G. (CRC1348/A04, GE514/6-3) and U.R. (CRC1009/A06, CRC1348/A11); the Interdisciplinary Center for Clinical Research of the Münster Medical School to U.R. (Re2/022/20); the Danish Council for Independent Research (6108-00378A, 9040-00252B), Scientific Committee Danish Cancer Society (R90-A5847-14-S2, R269-A15812), and the Novo Nordisk Foundation (NNF18OC0034936) to J.N.; the Royal Society and Wolfson Foundation (RSWF\R3\183001) to F.N.E.G.; the National Institute of Health (NIH R01AR055686) to J.K.J.; the Ara Parseghian Medical Research Fund (G217137) to T.G
