Worldwide, the majority of patients with advanced non-small-cell lung cancer (NSCLC) do not have activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). These wild-type patients comprise a significant proportion of those treated with inhibitors of this pathway, and data from randomized trials suggest that some of these wild-type patients will derive a modest benefit from these agents. Although the detection of an activating mutation predicts for a greater likelihood of response and longer progression-free survival from an EGFR tyrosine kinase inhibitor, currently there are no biomarkers that consistently and reproducibly predict for lack of benefit in wild-type patients. Several strategies to increase the efficacy of these inhibitors in wild-type NSCLC are the subject of ongoing investigations.