In the early 1970s, the hypothesis that tumor growth is dependent on angiogenesis was first established [1]. Since then, the role played by blood vessels in tumor growth and progression has been extensively studied and debated. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of disease in various tumor types including squamous cell carcinoma of the head and neck (SCCHN), of which close to 38,500 new cases are diagnosed each year. In SCCHN, the role of anti-angiogenic therapy has yet to be defined. Traditional therapy of SCCHN has involved a multimodality approach with radiotherapy, surgery as well as chemotherapy. More recently, novel therapeutic agents have been subject to preclinical and clinical development, among which anti-angiogenic therapy has gained much recent interest. In this critical review, we give an overview of angiogenesis and its potential therapeutic targets, and we focus on its preclinical and clinical applications in SCCHN.