Given the well-established role of EGFR as a driver oncogenic kinase in many cancer types, coupled with the need to improve EGFR-targeting strategies in the clinic and the dependence on phosphorylation of C-terminal tyrosines for signal propagation, we took a mechanistic, phosphoproteomics-based approach to investigate the contribution of individual EGFR C-terminal tail tyrosines to the EGFR signaling network. The gene discussed is EGFR; the disease is cancer.