Many of the leading developments in management of non-small cell lung cancer (NSCLC) have been provided by the integration of specific targeted therapies either in combination with a backbone of standard chemotherapy or as a single agent. Agents that inhibit a specific pathway, such as that triggered by the activity of the epidermal growth factor receptor, or a regulatory process like angiogenesis, have made it possible to markedly increase response rates and extend survival, sometimes dramatically, along with a favorable therapeutic index. However, these novel therapies have established clinical benefit thus for only in the setting of incurable, advanced NSCLC. The value of these strategies in not only extending survival but potentially improving the cure rate when added to, or substituting for, conventional chemotherapy in the setting of early-stage resectable NSCLC or locally advanced NSCLC remains to be determined. A wide range of clinical trials for these settings have been pursued, with several pivotal studies still ongoing, and will be reviewed for their potential to redefine our current standards of care for potentially curable NSCLC through the integration of targeted therapies.