Epidermal growth factor receptor (EGFR) mutations define a subset of non-small cell lung cancers that are sensitive to EGFR-targeted tyrosine kinase inhibitors (TKIs). Treatment with EGFR TKIs improves outcomes for patients whose tumors harbor these mutations, but their efficacy is limited by the development of acquired resistance. The secondary gatekeeper mutation, T790M, is the most common resistance mechanism observed in patients who progress on erlotinib and gefitinib, and a new class of drugs has recently been developed to target mutant EGFR and T790M. Here, we review the latest data with each generation of EGFR inhibitors and discuss emerging resistance mechanisms that have been observed in patients who have progressed on the latest class of EGFR TKIs. Looking ahead, combination treatment strategies in the frontline and resistant setting may be required to promote more durable responses and delay the development of resistance, and longitudinal analyses of plasma circulating tumor DNA may allow for earlier detection of emerging resistance mutations.