Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has multiple effects on the vascular endothelium and many other cells. Many cancers utilize VEGF for proliferation, progression and metastasis, making it a logical target of anti-tumor therapy. Numerous clinical oncology trials have employed this therapeutic approach to effectively treat various malignancies. Hypertension has emerged as one of the most important adverse effects of anti-VEGF therapy. This is supported by multiple clinical trials, using either anti-VEGF antibody, or small molecules targeting VEGF receptor tyrosine kinases. The incidence of hypertension associated with anti-VEGF antibody therapy ranges from 11 to 32% in most phase III clinical trials, while the incidence is about 16 to 43% with therapy targeted at VEGF receptors. The mechanisms underlying anti-VEGF associated hypertension are not understood. Several potential mechanisms have been proposed including vascular rarefaction, endothelial dysfunction, altered nitric oxide metabolism and aberrant neurohormones. More importantly, anti-VEGF related hypertension may have significant clinical implications. Poorly controlled hypertension may be associated with worsening cardiac and renal function, and reversible posterior encephalopathy syndrome. Further studies should focus on uncovering the mechanisms of anti-VEGF induced hypertension, as well as guiding therapy for this adverse effect.