Ca-activated endocytosis involves three distinct processes. (1) Large Ca transients cause long-term changes of the outer plasmalemma monolayer that promote endocytosis (Hilgemann and Fine, 2011). Possible mechanisms include the generation of lipids that promote the growth of lipid domains (i.e., the coalescence of small domains to large domains) and/or the translocation of such lipids to the outer monolayer. (2) In synergy with spermidine, high cytoplasmic Ca causes inner monolayer changes that promote endocytosis. One possible mechanism is the coalescence of lipid domains by Ca- and lipid-binding proteins (e.g., annexins) (Chasserot-Golaz et al., 2005). (3) After membrane modification by Ca, the ATP-dependent synthesis of PIP₂ promotes MEND by Ca-independent mechanisms. The clustering of PIP₂ and PIP₂-binding proteins may promote transbilayer domain coupling and membrane buckling that in turn drives endocytosis.