Vascular endothelial growth factor (VEGF) is a rational target for advanced non-small cell lung cancer (NSCLC), a hypothesis validated by the recent Eastern Cooperative Oncology Group E4599 trial showing that the addition of the VEGF monoclonal antibody bevacizumab to chemotherapy prolongs overall survival. Several new tyrosine kinase inhibitors targeting the VEGF pathway are currently in advanced clinical development for NSCLC and offer several possible advantages compared with monoclonal antibodies, including oral administration, more flexible dosing, a broader spectrum of target inhibition, and different toxicity profiles. Among these agents, vandetanib (ZD6474), an inhibitor of the VEGF receptor (VEGFR)-2 and epidermal growth factor receptor tyrosine kinase, has been the most extensively studied. In a randomized phase II study of patients with platinum-refractory NSCLC, including squamous histology, vandetanib prolonged progression-free survival compared with gefitinib. In another phase II trial, an improvement in progression-free survival was observed for vandetanib in combination with docetaxel compared with docetaxel alone. AZD2171 is an inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 and other tyrosine kinases that has shown clinical activity in NSCLC in combination with carboplatin and paclitaxel. Several phase III trials are under way testing these agents either as monotherapy or in combination with chemotherapy in patients with lung cancer. Early results with these agents, and others being tested, raise the possibility that there will eventually be multiple VEGF-targeted therapies available in the clinic that can potentially benefit a broader range of patients with advanced-stage NSCLC.