Endocytosis driven by lipidic forces: a hypothesis. (1) The outer monolayer consists of Lo and Ld domains of small size and equal prevalence. Lipids diffuse rapidly between domains, with affinity differences for Lo versus Ld domains being less than one log unit. “Lipid shells” around membrane proteins (Anderson and Jacobson, 2002) need not be synonymous with Lo and Ld domains. (2) Nonionic amphipaths expand Ld domains and promote cap formation with buckling of the plasmalemma, which is associated with domain coalescence and protein sorting. Ca transients may trigger the generation of endocytosis-promoting lipids and their movement into the outer monolayer (Hilgemann and Fine, 2011; Lariccia et al., 2011). (3) Membrane internalization. Coalescence of Lo domains within expanded Ld domains promotes negative curvature, vesiculation, and fission without adapters or dynamins, similar to the generation of ceramide domains via SMases (Lariccia et al., 2011). Nonionic amphipaths remain in Ld domains at the cell surface. (4) MEND generates vesicles that follow normal trafficking pathways to endosomes with recycling back to the plasmalemma via ATP-dependent processes that are inhibited by NEM and oxidative stress.