The success of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab in numerous tumor types including non-small-cell lung cancer (NSCLC) has spurred the development of additional novel antiangiogenic agents with distinct mechanisms of action. These include the small-molecule receptor tyrosine kinase (TK) inhibitors ZD6474, sorafenib, sunitinib malate, and AG-013736, all of which inhibit VEGF receptor TK activity. Because of the structural similarity of the different receptor TKs, these receptor TK inhibitors inhibit multiple receptors in addition to VEGF receptor. Vascular endothelial growth factor Trap, a novel, high-affinity molecule with specificity to the VEGF molecule, was generated as a fusion molecule of the VEGF receptor extracellular domain and the Fc portion of immunoglobulin (Ig) G1. Data from phase I/II trials have indicated the clinical feasibility of these agents, which are currently being investigated in phase II/III trials.