The nicotinic acetylcholine receptor (nAChR) is regulated by changes in the host lipid bilayer composition and has been studied extensively to elucidate the relative importance of specific lipid-protein interactions versus more general nonspecific bilayer-protein interactions in the regulation of membrane protein function. Experiments reported in this issue provide strong support for the importance of lipid bilayer physical properties and lipid bilayer–membrane protein hydrophobic mismatch in the regulation of nAChR function.