The presence of gain-of-function somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene defines the first molecular subset of metastatic NSCLC patients whose tumors have 60–84% response rate to first-line EGFR tyrosine kinase inhibitors (TKIs; i.e., erlotinib, gefitinib, afatinib, osimertinib). The gene discussed is EGFR; the disease is non-small cell lung carcinoma.