Integrins are a family of cell-extracellular matrix adhesion molecules that play important roles in tumor angiogenesis. αvβ3-Integrin has received much attention as a potential anti-angiogenic target because it is upregulated in tumor-associated blood vessels. Agents targeting αvβ3-integrin are now showing some success in phase III clinical trails for the treatment of glioblastoma, but the exact function of this integrin in tumor angiogenesis is still relatively unknown. This review highlights some of the recent data illustrating that β3-integrins play both pro-angiogenic and anti-angiogenic roles in tumor angiogenesis depending on the context. Specifically we will discuss how the following differentially influence β3-integrin's role in tumor angiogenesis: first, cell-matrix interactions, second, β3-integrin inhibitor doses, third, cell type, and fourth, other interacting molecules.