The regulation of angiogenesis is fundamental to a variety of physiological and pathological processes. Although a number of factors have been identified that induce neovascularization, it is becoming increasingly apparent that endogenous angiostatic factors may play an important role in the regulation of angiogenesis during wound repair, chronic inflammation, and growth of solid tumors. In this review, we demonstrate that the CXC chemokine family of cytokines display disparate angiogenic activity depending upon the presence or absence of the ELR motif, a structural amino acid motif previously found to be important in receptor ligand binding on neutrophils. CXC chemokines containing the ELR motif are potent angiogenic factors, inducing both in vitro endothelial chemotaxis and in vivo corneal neovascularization. In contrast, the CXC chemokines that lack the ELR motif, PF4, IP-10, and MIG, not only fail to induce significant in vitro endothelial cell chemotaxis or in vivo corneal neovascularization, but are found to be potent angiostatic factors in the presence of CXC chemokines containing the ELR motif. These findings suggest that the CXC chemokine family can display disparate angiogenic activity that depends upon the presence or absence of the ELR motif. Furthermore, these studies support the notion that the net biological balance in the magnitude of expression of angiogenic and angiostatic CXC chemokines at either the site of wound repair or during tumorigenesis may be important in the regulation of net angiogenesis.