Abstract: The epidermal growth factor receptor (EGFR) interacts through its extracellular domain (ECD) with seven different growth factors. These factors induce different structures within the cytoplasmic juxtamembrane segment (JM) of the dimeric receptor and propagate different growth factor-dependent signals to the cell interior. How this process occurs is unknown. This lecture will describe the application of chemical and biological tools to study and define long-range conformational changes within EGFR that encode ligand identity on the cell surface and TKI identity and mutational status within the kinase domain. Our studies reveal direct correlations between growth factor identity, transmembrane helix population, JM coiled coil conformation, downstream signaling, and accurately EGFR lifetime. These findings provide insight into how multi-domain membrane proteins decode and transmit distinct extracellular signals, and how these events can be modulated with designed ligands.