Novel therapies have been added to the treatment arsenal of physicians treating lung cancer in recent years. Most promising are agents that target the major pathways involved in cancer evolution, mostly proliferation and angiogenesis. Some of these treatments have been shown to synergize with traditional chemotherapy and radiation therapy. Multitargeted therapy seems to be the next step of advancement in the treatment of lung cancer. This can refer not only to molecules that autonomously inhibit several pathways but also to combinations of therapies that, by targeting more than one pathway, act in concert to inhibit the malignant growth. In this review, we present the background and current status of multitargeted treatments in the management of patients with lung cancer, mostly non-small-cell lung cancer (NSCLC). Novel agents in clinical use and important ongoing clinical trials are reviewed.