Antiangiogenic therapy inhibits tumor growth by targeting the blood vessels of the tumor. Antiangiogenic therapy often correlates with longer survival in patients without affecting tumor growth. This positive response may be due to the off-tumor target effects of antiangiogenic drugs. In this article, Yihai Cao describes the potential mechanisms underlying the benefits of targeting off-tumor sites, and how these events improve outcomes in patients with cancer-associated systemic syndromes.