Angiogenesis is an important tissue-level program supporting the growth of highly aggressive cancers and early-stage metastases. However, rapid emergence of resistance to antiangiogenic therapies, such as bevacizumab, greatly limits the clinical utility of these promising approaches. The mechanisms of resistance to antiangiogenic therapy remain incompletely understood. The tumor microenvironment has been demonstrated to be a source of broad therapeutic resistance in multiple cancers. Much of the interaction between the cells comprising a tumor and their microenvironment is driven by integrins. Notably, signaling downstream of integrins in tumor cells promotes fundamental programs vital to aggressive cancer biology, including proliferation, growth, invasion, and survival signaling. These functions then can contribute to malignant phenotypes, including metastasis, therapy resistance, epithelial-to-mesenchymal transition, and angiogenesis. Accordingly, we found β1 integrin to be functionally upregulated in tumor specimens from patients after bevacizumab failure and in xenograft models of bevacizumab resistance. Inhibition of β1 in tumor cells with stable gene knockdown or treatment with OS2966, a neutralizing β1 integrin monoclonal antibody, attenuated aggressive tumor phenotypes in vitro and blocked growth of bevacizumab-resistant tumor xenografts in vivo. Thus, β1 integrins promote resistance to antiangiogenic therapy through potentiation of multiple malignant programs facilitated by interactions with the tumor microenvironment. The elucidation of this mechanism creates an outstanding opportunity for improving patient outcomes in cancer. Cancer Res; 74(1); 3–7. ©2013 AACR.