Lipids on the plasma membrane are not only components of the membrane biophysical structures but also regulators of receptor functions. Recently, the critical roles of lipid-protein interactions have been intensively highlighted. Epidermal growth factor receptor (EGFR) is one of the most extensively studied receptors exhibiting various lipid interactions, including interactions with phosphatidylcholine, phosphatidylserine, phosphatidylinositol phosphate, cholesterol, gangliosides, and palmitate. Here, we review recent findings on how direct interaction with these lipids regulates EGFR activation and signaling, providing unprecedented insight into the comprehensive roles of various lipids in the control of EGFR functions. Finally, the current limitations in investigating lipid-protein interactions and novel technologies to potentially overcome these limitations are discussed.