Inhibitors targeting the epidermal growth factor receptor (EGFR) are effective in a subset of non-small cell lung cancers. Such cancers often harbor EGFR mutations and/or amplification. These cancers require EGFR activity for the maintenance of critical intracellular survival and growth signaling pathways. Evidence is now accruing that EGFR works in concert with other ErbB family members, particularly HER2 and ErbB3, to activate these signaling pathways in lung cancers. These findings have important implications regarding the biology of these cancers and may lead to improved methods for identifying tumors that are responsive to EGFR kinase inhibitors and alternative therapies to treat cancers driven by ErbB signaling.