Integral membrane proteins that are embedded in the cellular plasma membrane make up the vast majority of all approved drug targets. However, the contributions of the membrane lipids to the function and behavior of these membrane-embedded proteins have for years been neglected. Often the membrane itself is seen as just a ‘scaffold’ to hold the protein in place. Using a range of integrated computational and experimental methods (several developed specifically for this project), we explore the interactions between membrane proteins and their surrounding lipid environments to reveal just how intricate, detailed, and balanced the relationship is.