Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.