The development of a tumor vasculature or access to the host vasculature is a crucial step for the survival and metastasis of malignant tumors. Although therapeutic strategies attempting to inhibit this step during tumor development are being developed, the biological regulation of this process is still largely unknown. Using a transgenic mouse susceptible to mammary cancer, PyMT mice, we have characterized the development of the vasculature in mammary tumors during their progression to malignancy. We show that the onset of the angiogenic switch, identified as the formation of a highdensity vessel network, is closely associated with the transition to malignancy. More importantly, both the angiogenic switch and the progression to malignancy are regulated by infiltrated macrophages in the primary mammary tumors. Inhibition of the macrophage infiltration into the tumor delayed the angiogenic switch and malignant transition whereas genetic restoration of the macrophage population specifically in these tumors rescued the vessel phenotype. Furthermore, premature induction of macrophage infiltration into premalignant lesions promoted an early onset of the angiogenic switch independent of tumor progression. Taken together, this study shows that tumor-associated macrophages play a key role in promoting tumor angiogenesis, an essential step in the tumor progression to malignancy. (Cancer Res 2006; 66(23): 11238-46)