There is a substantial literature from the 1970s, often overlooked by many present workers, on the physical chemistry of lipid bilayer systems, which have laid the foundation for studying lateral organization and lipid domains in membranes (for a critical review, see Ref. 1). Early evidence that lipids could laterally segregate in model membrane systems under certain conditions and form different lipid domains with particular structural characteristics (i.e., different lateral packing) was reported in 1970 by Phillips et al.,² who assessed, using differential scanning calorimetry (DSC), the lateral mixing of different glycerophospholipid species; in 1973 by Shimshick and McConnell,³ who explored lipid lateral phase separation by using electron paramagnetic resonance (EPR); in 1974 by Grant et al.,⁴ who observed lipid domains by freeze-fracture electron microscopy; and in 1976 by Lentz et al.,⁵ who demonstrated nonideal mixing among different glycerophospholipids containing saturated and unsaturated chains using fluorescence anisotropy. Detailed nuclear magnetic resonance (NMR) studies of sphingomyelin (SM) in bilayers by Schmidt et al.⁶ in 1977 prompted the hypothesis that sphingolipids might form microdomains in biological membranes. Also in 1977, Gebhardt et al.⁷ considered the lipid compositional heterogeneity in natural membranes and predicted that lipid lateral segregation might arise under particular environmental conditions such as those that mimic a physiological state. In a similar manner, Marcelja⁸ in 1976 and Sackmann⁹ in a classical review from 1984 anticipated the possible role of different membrane regions induced by lipid–protein interactions as a physical basis for membrane-mediated processes. This discussion was repeatedly addressed on several occasions by various researchers.^10–13 Yet, the view of the main structural/dynamical features of biological membranes was profoundly influenced and to a significant extent biased by the fluid mosaic model proposed in 1972 by Singer and Nicolson.¹⁴ The fluid mosaic model, which to date is the most influential model for biological membranes, supports the idea of lipids forming a more or less randomly organized bidimensional fluid matrix where proteins perform their distinct functions. Although lipid-mediated lateral heterogeneity in membranes was simultaneously described during the 1970s, this feature was not considered in the Singer and Nicolson model.