Lung cancer is the leading cause of cancer-related death in the United States. Despite the availability of several cytotoxic and a few molecularly targeted agents, the outlook for patients with advanced non-small cell lung cancer continues to be dismal. Novel approaches are desperately needed. The insulin-like growth factor (IGF) pathway plays an important role in a number of human malignancies contributing to unregulated cell proliferation. The IGF pathway has several targets for therapeutic intervention. Preclinical studies of IGF inhibitors have demonstrated synergism when combined with chemotherapy agents and radiation. Clinical studies are currently ongoing to investigate the safety and efficacy of IGF inhibitors in combination with chemotherapy agents. In this review, we discuss the biology of the IGF pathway and various potential targets for therapy.