Recent crystallographic studies have offered a new understanding of how receptor tyrosine kinases from the ErbB family are regulated by their growth factor ligands. A large conformational change was shown to occur upon ligand binding, where a solely receptor‐mediated mode of dimerization was documented. We have shown that oxidative stress, in the form of H2O2, activates the epidermal growth factor (EGF) receptor (EGFR, ErbB1) in human airway epithelial cells differently than its ligand, EGF. Most notably, H2O2 activation of the EGFR resulted in aberrant phosphorylation as well as impaired trafficking and degradation of the receptor, which leads to hyperplasia. Using various biochemical techniques, we now demonstrate that H2O2 activation of the EGFR is ligand‐independent and does not induce receptor dimerization in the same manner as EGF. Interestingly, H2O2−induced phosphorylation of the EGFR is not inhibited by the EGFR kinase inhibitors AG1478 and AG1517, which may negatively impact therapies targeting the kinase domain. Furthermore, H2O2 activation of the EGFR is temperature‐dependent and is inhibited by the addition of cholesterol, suggesting that activation by H2O2 is dependent upon membrane fluidity. Overall, our findings indicate that H2O2 activation of the EGFR does not fit the current paradigm of activation by EGF. By combining the information gained from the recent biochemical studies, we hope to develop models for the allosteric regulation of the EGFR under oxidative stress. These models will greatly improve our understanding of ErbB receptor signaling under oxidative stress, which will generate opportunities for the design of new anticancer agents.