Small molecule ligands regulate the conformation, stability and function of many membrane proteins. They are sometimes “hinted” in cryo-EM and crystallography studies but cannot be chemically defined. Using the latest advances in Tribrid Mass Spectrometry, we have developed "Nativeomics", a novel top-down method unifying "omics" (lipidomics, proteomics, metabolomics) with native MS analysis, to identify endogenous ligands specifically bound to membrane protein assemblies. By maintaining the link between proteins and binding partners, we can define the lipidome/metabolome in contact with membrane protein assemblies to discover previously unknown complexes, new endogenous ligands and regulators of protein function.