Protein kinases are key players in signal transduction pathways where they are crafted into two functional states. In response to growth factor binding stimulus, epidermal growth factor receptor (EGFR), which is physiologically populated in an autoinhibited inactive state, becomes active. Here, we outline a simple allostery scheme to clarify how an extracellular (ligand-dependent) binding event activates the intracellular EGFR kinase domain via (dimer-dependent) asymmetric dimerization, as well as how pathologically overexpressed EGFR or constitutively active mutants, leads to oncogenic pathway activation. Our underlying allosteric activation mechanism derives from a collection of inactive versus active EGFR structural, biochemical (negatively cooperative ligand binding), and biophysical (weak coupling between extracellular and intracellular kinase dimerization) data. The emerging structural insight reveals that ligand-dependent physiological activation is an outside-in allosteric activation with strong structural coupling across the membrane. In contrast, ligand-independent pathological activation is a weak inside-out activation mediated by intracellular kinase dimerization, which is structurally accommodated by additional extracellular dimers.