Tumor angiogenesis is a hallmark of advanced cancers and an attractive treatment target in multiple solid tumors. In the past 5 years anti-angiogenic therapies have seen a rapid ascent into mainstream clinical practice. For head and neck cancer (HNC), definitive evidence in the form of a pivotal trial is still pending. Nevertheless, preclinical and early clinical data support a central role of angiogenesis for HNC: up to 90% of HNCs express angiogenic factors such as vascular endothelial growth factor (VEGF) and the respective receptors (VEGFR1-3), and multiple studies support the prognostic implications of angiogenic markers for this tumor. Contrary to concerns that anti-angiogenic therapies could increase hypoxia and thereby treatment resistance, anti-angiogenic therapies in preclinical models appear to overcome resistance and preclinically synergize with traditional therapies, eg, radiation. Clinical use of anti-angiogenic agents for HNC, including bevacizumab, sorafenib, sunitinib, and others, is currently limited to clinical trials, and several larger trials are still ongoing. Single-agent anti-angiogenic drugs so far have not shown activity in unselected HNC patients, with a response rate of less than 4% for the small molecule anti-angiogenics sorafenib and the investigational agent SU5416. On the other hand, combinations of anti-angiogenic drugs with other treatments (analogous to other solid tumors) appear promising; for example, the combination of bevacizumab with the EGFR inhibitor erlotinib showed a response rate of 14.6%. Studies of bevacizumab with chemotherapy (phase III Eastern Cooperative Oncology Group [ECOG] trial) and in combination with chemoradiation are currently ongoing. The side effect profile is comparable to what has been observed in other tumor types and include hypertension, proteinuria, and thrombotic and hemorrhagic events. With the intense research effort preclinically and clinically, and some encouraging early results, anti-angiogenic therapies and biomarkers appear to be poised to play an important role in the treatment of HNC in the near future.