A large body of evidence strongly indicates biomembranes to be organized into compositionally and functionally specialized domains, supramolecular assemblies, existing on different time and length scales. For these domains and intimate coupling between their chemical composition, physical state, organization, and functions has been postulated. One important constituent of biomembranes are peripheral proteins whose activity can be controlled by non-covalent binding to lipids. Importantly, the physical chemistry of the lipid interface allows for a rapid and reversible control of peripheral interactions. In this review examples are provided on how membrane lipid (i) composition (i.e., specific lipid structures), (ii) organization, and (iii) physical state can each regulate peripheral binding of proteins to the lipid surface. In addition, a novel and efficient mechanism for the control of the lipid surface association of peripheral proteins by [Ca2+], lipid composition, and phase state is proposed. The phase state is, in turn, also dependent on factors such as temperature, lateral packing, presence of ions, metabolites and drugs. Confining reactions to interfaces allows for facile and cooperative large scale integration and control of metabolic pathways due to mechanisms which are not possible in bulk systems.