For solid tumours to grow and spread they produce cytokines and growth factors that promote the recruitment of host vasculature and bone marrow (BM) derived endothelial progenitor cells (EPCs). The small molecule chemokine, CCL5 has recently been associated with tumour growth and malignancy in breast cancer (1). However, the specific role of CCL5, and in particular its high affinity receptor CCR5 in tumour vascular biology, is less certain. Here, we show that breast tumours grown in CCR5 null mice display tumour growth and angiogenesis defects; as well, tumour challenged mice exhibit a specific EPC proliferation defect. However, when BM from CCR5 null animals was transplanted into WT mice, normal tumour growth and angiogenesis was rescued. In contrast, CCR5 null mice transplanted with wild type BM phenocopied the tumour growth defects observed in the whole CCR5 knockout animal. This result suggested that tumour growth and angiogenesis defects in the knockout animal are principally due to the non-BM compartment of the tumour stroma. Notably, stable suppression of tumour CCL5 led to increased tumour cell growth in vitro, however, distinctive tumour growth and angiogenesis defects were noted in vivo, suggesting a paracrine role for CCL5 signalling. In further studies, we have found induction of CCR5 in human and mouse endothelial cells in response to tumour conditioned medium. Furthermore, we have identified CCR5 expression in tumour vasculature in two different breast cancer models in situ. Targeting CCR5 led to significant wound healing and angiogenesis defects in vitro. Directly targeting CCL5/CCR5 in endothelial cells may constitute a novel strategy for inhibiting tumour angiogenesis in breast cancer.