The most widely studied of the antiangiogenic agents is bevacizumab (Avastin; Genentech; South San Francisco, CA), a humanized mAb that binds all isoforms of VEGF. Several clinical trials have evaluated the efficacy of bevacizumab therapy in patients with recurrent or advanced NSCLC. In 2004, a randomized phase II trial56(99 patients) demonstrated that the addition of bevacizumab to a standard chemotherapy regimen (eg, paclitaxel plus carboplatin) increases the median survival and response rates significantly in patients with advanced NSCLC. Unfortunately, a significant increase in the rate of pulmonary hemorrhage was observed with the addition of bevacizumab, particularly in those patients with squamous-type NSCLC. A subsequent phase III trial57 (878 patients), which excluded NSCLC of squamous type, demonstrated similar improvements in response and survival rates with the addition of bevacizumab to therapy with paclitaxel plus carboplatin for the treatment of recurrent or advanced NSCLC. In this study, there were 17 deaths related to therapy, 2 in the paclitaxel-plus-carboplatin group and 15 in the bevacizumab-paclitaxel-carboplatin group, which included 5 deaths attributed to pulmonary hemorrhage. Despite this, the therapeutic regime studied in the phase III trial (E4599) has been adopted as the Eastern Cooperative Oncology Group standard of care for first-line treatment of advanced NSCLC. However, it is clear that the benefits should be carefully balanced with the increased risk of treatment-related death for each patient. Further trials are underway to evaluate the efficacy of bevacizumab when used with other chemotherapy agents. In addition to monoclonal anti-VEGF therapy, small-molecule TKIs that nonselectively target VEGFR have been developed, including sorafenib, vatalanib, and sunitinib. These agents are currently in phase II/III evaluation for the treatment of advanced NSCLC.