Annexins are a highly conserved protein family that bind to phospholipids in a 
calcium (Ca2+) - dependent manner. Studies with purified annexins, as well as 
overexpression and knockdown approaches identified multiple functions 
predominantly linked to their dynamic and reversible membrane binding behavior. 
However, most annexins are found at multiple locations and interact with 
numerous proteins. Furthermore, similar membrane binding characteristics, 
overlapping localizations and shared interaction partners have complicated 
identification of their precise functions. To gain insight into annexin function 
in vivo, mouse models deficient of annexin A1 (AnxA1), A2, A4, A5, A6 and A7 
have been generated. Interestingly, with the exception of one study, all mice 
strains lacking one or even two annexins are viable and develop normally. This 
suggested redundancy within annexins, but examining these knockout (KO) strains 
under stress conditions revealed striking phenotypes, identifying underlying 
mechanisms specific for individual annexins, often supporting Ca2+ homeostasis 
and membrane transport as central for annexin biology. Conversely, mice lacking 
AnxA1 or A2 show extracellular functions relevant in health and disease that 
appear independent of membrane trafficking or Ca2+ signaling. This review will 
summarize the mechanistic insights gained from studies utilizing mouse models 
lacking members of the annexin family.