Approximately one third of non-small cell lung cancer (NSCLC) patients will present with locally advanced, stage III disease. With the use of pretreatment positron emission testing and mediastinal lymph node sampling, classifying stage III NSCLC has become more involved and treatment strategies have shifted from single modality thoracic radiation to combined chemoradiotherapy. This article reviews evidence-based strategies in the treatment of locally advanced NSCLC and presents new efforts for improving the poor prognosis of this disease by incorporating novel chemotherapy and biologic based regimens.