While current membrane models include detailed descriptions, one fundamental aspect that remains underexplored is physical chemistry of membranes with biological compositions, which typically contain hundreds to thousands of lipid species when considering the diversity in headgroups and acyl chain structures. Why so many lipids? This question remains largely unresolved since biochemical approaches to addressing this question have provided mainly indirect information, and the complex interplay between local lipid composition and membrane protein topology as well as colocalization can be particularly complex . The fundamental interactions are well understood: headgroup dipole-dipole interactions, hydrogen bonding between headgroups and with interfacial water, tail packing, and steric effects. Recent techniques and experiments, described below, have begun to shed light on the interplay between acyl chain composition and general trends in membrane protein topologies, but fundamental questions remain unaddressed. Specific questions include: how the balance of forces between lipid-lipid, lipidprotein, and lipid-water interactions, together with packing, dictates the local membrane environment in membranes containing thousands of lipids. Figure shows a schematic representation of different lipid structures to emphasize on the diversity in headgroup structures and highlight hydrogen-bond donors and acceptors, and the steric size of the headgroup, as well as positive and negative charges associated with different functional groups. In brief, this depiction stresses the complex hydrogen bonding interactions present in multicomponent membranes. The main challenges to achieving a molecular-level understanding stem largely from the lack of well-controlled model systems that incorporate lipid diversity and a range of local interactions, which can be combined with the dearth of experimental techniques to probe species-specific interactions, molecular conformations, and local environments in multicomponent bilayers.