Within the past 2 years, epidermal growth factor receptor (EGFR) inhibitors have moved from experimental agents to approved drugs for the management of advanced non-small cell lung cancer (NSCLC). This evolution has been accompanied by dramatic improvements in the understanding of how these drugs work and the clinical populations that may benefit. The identification of mutations in the ATP-binding domain of the EGFR that predict for dramatic responses introduces the possibility of truly individualized therapy in a subset of advanced NSCLC patients. The fact that these mutations may be more prevalent in certain patient populations, including patients of Asian ethnicity, female gender, and never-smoker status, raises intriguing questions regarding the pathogenesis of lung cancer. Another emerging area in the understanding of these agents revolves around the clinical observation that acneform rash may predict for superior outcome and the question of how this rash may relate to polymorphisms in the EGFR gene. EGFR polymorphisms, both germline and somatic, may be a relevant factor in unraveling the mechanism of the benefit of erlotinib in patients who do not harbor an EGFR ATP-binding site mutation. Numerous questions have arisen regarding how to best incorporate EGFR-targeted agents into patient management, as well as the role of the clinical laboratory in these decisions and the design of future trials.