-arrestins (-Arrs) are known to be associated with tumor signaling pathways such as transforming growth factor-1 (TGF-1), P53/monocyte-derived macrophages (MDM2) and NF-B. To investigate the role of -Arr in tumor progression in vivo, we generated -Arr transgenic mice by subcutaneously inoculating tumor cells in them. We found that the xenograft tumor initiated earlier and grew more rapidly in -Arr1 transgenic mice than in both the -Arr2 transgenic and wild-type mice after inoculating murine liver cancer Hepa1–6 cells or lymphoma EL4 cells. Moreover, matrix metalloproteinase 9 (MMP9) activity, vascular endothelial growth factor (VEGF) concentration in plasma and new small blood vessel formation in tumor tissues were enhanced in -Arr1 transgenic mice compared with those in control mice. In addition, injection of MMP9 inhibitors in -Arr1 transgenic mice abrogated all these effects and suppressed rapid tumor progression. Similar results were observed in human microvascular endothelial cells, where overexpressed -Arr1 did increase MMP9 activity and small blood vessel formation. Furthermore, phosphatidylinositol 3-kinase (PI3K) inhibitors could suppress -Arr1-enhanced MMP9 activity and the C-terminal 181–418 amino acids (aa) of -Arr1 was largely responsible for this effect. Our data reveal a functional role for -arrestin1 in tumor progression in vivo, in which overexpression of -Arr1 promotes MMP9 activity and tumor angiogenesis by providing a suitable microenvironment for tumor progression.—Zou, L., Yang, R., Chai, J., Gang Pei. Rapid xenograft tumor progression in beta-arrestin1 transgenic mice due to enhanced tumor angiogenesis.