Biomembranes constitute the physical boundaries of individual cells and provide a stage for MPs to play their functional roles. How do the cell membrane and its lipid composition stabilize MPs in the correct physiological conformation and provide the driving force for their functions? What is the relationship between the structures of MPs determined by in vitro structural biology experiments and their physiological conformation ensembles in vivo? This chapter analyzes the interaction between MPs and the environment from the perspective of biomembranes, focusing on concepts such as hydrophobic mismatch and trans-membrane electrostatic potential.