Angiogenesis, the expansion of preexisting blood vessels, is a complex process required for tumor growth and metastasis. Although current antiangiogenic strategies have shown promising results in several cancer types, identification of additional antiangiogenic targets is required to improve the therapeutic response. Herein, we show that the microtubule-binding protein CLIP-170 (cytoplasmic linker protein of 170 kDa) is highly expressed in breast tumor samples and correlates positively with blood vessel density. Depletion of CLIP-170 significantly impaired vascular endothelial tube formation and sprouting in vitro and inhibited breast tumor growth in mice by decreasing tumor vascularization. Our data further show that CLIP-170 is important for the migration but not the proliferation of vascular endothelial cells. In addition, CLIP-170 promotes the polarization of endothelial cells in response to the angiogenic stimulus. These findings thus demonstrate a critical role for CLIP-170 in tumor angiogenesis and suggest its potential as a novel antiangiogenic target.