A variety of factors cooperate to regulate neovessel formation and persistence. Proangiogenic growth factors have remained an area of intense interest due to their capacity to promote endothelial cell (EC) proliferation and to initiate the angiogenic program. These growth factors are associated with increased cell survival, yet paradoxically, angiogenic ECs are more susceptible to apoptosis than quiescent ECs. Survival is regulated by cooperation between growth factor receptors and integrins, which are in turn governed by the composition of the local extracellular matrix (ECM). Integrin-mediated signaling is altered or disrupted by the presence of soluble, rather than matrix-bound ligands, thus providing a means by which ECM remodeling can influence both integrin- and growth factor-mediated events. Ultimately, the collaboration of these factors determines whether ECs survive or die, thereby regulating neovascularization.