Non–small-cell lung carcinoma is a leading cause of cancer deaths in the United States and worldwide. Historically, diagnostic classification and treatment decisions were based on a simple algorithm that considered only the distinction from small cell carcinoma and tumor stage. However, we are increasingly recognizing the histologic and molecular heterogeneity of lung cancers and are developing more effective targeted therapies as a result. Use of targeted epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy is one of the great successes in this regard. The presence of somatic EGFR activating mutations appears to be the best predictor of response to this targeted therapy. This review recaps the rationale behind the development of EGFR tyrosine kinase inhibitors and offers some historical perspective on the clinical experience with these drugs. Finally, we provide some guidelines to the practicing pathologist regarding currently available techniques for mutation analysis as well as a discussion of alternate modalities for assessing EGFR receptor activation in tissue samples.