β‐arrestins (β‐Arrs) are known to be associated with tumor signaling pathways such as transforming growth factor‐β1 (TGF‐β1), P53/Murine double minute (MDM2) and NF‐κB. To investigate the role of β‐Arr in tumor progression in vivo, we generated β ‐Arr transgenic mice by subcutaneously inoculating tumor cells in them. We found that the xenograft tumor initiated earlier and grew more rapidly in β‐Arr1 transgenic mice than in both the β‐Arr2 transgenic and wild‐type mice after inoculating murine liver cancer Hepal‐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 β‐Arr1 transgenic mice compared with those in control mice. In addition, injection of MMP9 inhibitors in β‐Arr1 transgenic mice abrogated all these effects and suppressed rapid tumor progression. Similar results were observed in human microvascular endothelial cells, where overexpressed β ‐Arr1 did increase MMP9 activity and small blood vessel formation. Furthermore, phosphatidylinositol 3‐kinase (PI3K) inhibitors could suppress β‐Arr1‐enhanced MMP9 activity and the C‐terminal 181–418 amino acids (aa) of β‐Arr1 was largely responsible for this effect. Our data reveal a functional role for β ‐arrestinl in tumor progression in vivo, in which overexpression of β‐Arr1 promotes MMP9 activity and tumor angiogenesis by providing a suitable micro environment 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. FASEB J. 22, 355–364 (2008)