Small molecule kinase inhibitors of the epidermal growth factor receptor (EGFR) have recently been found to exhibit clinical efficacy in the setting of nonsmall cell lung cancers that harbor activating EGFR mutations. However, the remissions induced by these drugs (Iressa and Tarceva) are typically short-lived, presumably due to acquired drug resistance. We recently reported findings demonstrating that a distinct class of EGFR inhibitors may overcome some mechanisms of secondary drug resistance in these tumors and may therefore be useful in treating lung cancer patients that initially responded to Iressa or Tarceva and eventually relapsed.