Lung cancer remains the leading cause of malignancy-related mortality world-wide, in both men and women, with over a million cases diagnosed yearly. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, and most patients are diagnosed with advanced disease. Although substantial progress has been made in the therapeutic options currently available for patients with advanced NSCLC, chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may safely and effectively be administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor receptor (VEGFR) plays an essential role in tumor angiogenesis and proliferation, and has been a major focus of basic research and drug development in the field of Oncology. Approaches targeting VEGFR include mainly small molecule inhibitors of VEGFR tyrosine kinase activity. Among these, vandetanib, due to early findings of its antitumor activity and a good toxicity profile, has been largely investigated in advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, and sunitinib are being tested in ongoing clinical trials which will further define their role in the management of NSCLC. Here we review the current results and give an overview of some of the future developments of the main anti-VEGFR drugs in the treatment of NSCLC patients.