The recent identification of somatic mutations in the epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) domain of tumor samples from patients with non-small-cell lung cancer (NSCLC) that portend robust response to small-molecule inhibitors of EGFR TK is a watershed event in the fields of lung cancer genetics and therapeutic agents. In addition to paralleling what is already known about c-kit mutations that drive the proliferation of gastrointestinal stromal tumors and their response to imatinib, and providing the possibility of prospectively selecting patients with NSCLC who have a high probability of responding to EGFR TK inhibitors, these reports will likely have much broader implications with regard to the optimal and most expeditious means to develop rationally designed, target-based therapeutic agents--first establishing proof of principle in patients whose malignancies are dependent or driven by aberrations of the therapeutic's target. These new findings will undoubtedly lead to a greater understanding of the biology of EGFR-mutant NSCLC and the mechanism of action of EGFR TK inhibitors. This further validates EGFR as a target for anticancer therapy, particularly in tumors with activating mutations of the target, which lead to sequencing of genes that govern other relevant proteins that are currently being targeted with novel therapeutic agents. The result should be more efficient and scientifically founded clinical development strategies for rationally designed target-based therapeutic agents.