Significance Dysregulation of both vascular architecture and function is a hallmark of numerous diseases, including cancer. This dysregulation is currently largely attributed to up-regulated proangiogenic growth factors. Here, we show that the stiffness of the underlying extracellular matrix also plays a central role in promoting angiogenesis and a characteristic tumor-like vasculature both in vitro and in vivo. The matrix stiffness-mediated angiogenesis is dependent on increased matrix metalloprotease activity. In addition, increased matrix cross-linking disrupts endothelial cell–cell junctional integrity and results in leakier vasculature. These results suggest that altered tissue mechanics, which are characteristic of solid tumors, directly influence vascular phenotype and, subsequently, may impair therapeutic delivery and efficacy.