Activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) in nonsmall cell lung cancers (NSCLCs) correlate with responsiveness to EGFR kinase inhibitors. In vitro cell culture studies have demonstrated that EGFR kinase domain mutants but not wild type (wt) EGFR are transforming and essential for cancer cell survival. We and others have recently demonstrated that the induction of EGFR kinase domain mutants specifically in murine lung epithelium in vivo led to development of adenocarcinoma with bronchioloalveolar carcinoma (BAC) features. These tumors depend completely on the sustained expression of EGFR kinase domain mutants for tumor maintenance. The murine tumors with EGFR kinase domain mutations are sensitive to EGFR targeted therapy similarly to NSCLC patients whose tumors harbor EGFR mutations. In contrast, initial results suggest that overexpression of wt EGFR in murine lungs does not seem to be transforming. We therefore divide EGFR targeted therapy in NSCLC patients into two parts: "EGFR mutant targeted therapy" and "wt EGFR targeted therapy". The "EGFR mutant targeted therapy" targets the oncogene essential for tumor initiation and maintenance and is frequently correlated with effective clinical outcome. In contrast, "wt EGFR targeted therapy" likely targets the proto-oncogene product wt EGFR, which is not directly involved in tumor initiation and maintenance, and in these cases, the response has been considerably less dramatic.