Tumor growth and metastasis are angiogenesis-dependent and tumor angiogenesis is a result of complex interplay of positive and negative regulators. Vascular endothelial growth factor (VEGF) occupies a particular place among the positive regulators of angiogenesis due to its potency and specificity for endothelial cells. VEGF upregulates several molecules such as growth factors, adhesion molecules, proteases, and protease receptors and it actually induces microvascular hyperpermeability, resulting in activation of thrombin from prothrombin. Osteopontin (OPN) is a secreted arginine-glycine-asparic acid (RGD)-containing phosphoprotein and it contains a predicted thrombin cleavage site. OPN binds to several integrins and CD44 variants. OPN has diverse functions such as cell adhesion, chemoattraction, and immunomodulation, and it induces endothelial cell migration and upregulates endothelial cell migration induced by VEGF. OPN expression is upregulated in human carcinomas. This review documents the functional roles of VEGF and OPN in angiogenesis and their clinical significance in tumor biology.