Chemokine signaling in breast cancer is complex. Members play important roles in modulating normal tissue homeostasis. Because of the complexity of signaling in the tumor-stroma, understanding the different roles that tumor chemokines play in breast cancer, and modulating chemokine signaling for therapeutic benefit has been challenging. It has recently been suggested that a key member of the family, CCL5/RANTES, is required for tumor angiogenesis in breast cancer. Here we show that suppression of either cancer cell produced CCL5, or host CCR5 leads to distinctive vascular and tumor growth defects in breast cancer. Surprisingly, CCR5 restoration in the bone marrow alone was not sufficient to rescue the wild type phenotype, suggesting that impaired tumor growth associated with inhibiting CCL5/CCR5 is not due to defects in bone marrow vascular biology. Instead, to promote angiogenesis cancer cell CCL5 may signal directly to endothelium in the tumor-stroma1. In support of this hypothesis we have also shown that the amount of CCR5+ tumor vasculature correlates with invasive grade; and that inhibition of CCL5/CCR5 signaling impairs endothelial cell migration, associated with a decrease in activation of mTOR/AKT pathway members. Finally, we show that treatment with CCR5 antagonist results in less vasculature, impaired tumor growth, reduced metastases and improved survival. Taken as a whole this work demonstrates that that directly inhibiting CCR5 expressing vasculature constitutes a novel strategy for inhibiting angiogenesis and blocking metastatic progression in breast cancer.