Small molecule inhibitors of endothelial cell specific tyrosine kinases are currently under investigation as potential means to block tumor angiogenesis. We have investigated the utility of blocking Tie-2 signaling in endothelial cells as a potential anti-angiogenic strategy. We have found that interruption of Tie-2 signaling either via RNAi or overexpression of a kinase-dead Tie-2 led to loss of endothelial cell viability, even in the presence of serum. Mechanistically, this is linked to a block in Akt signaling and increased thrombospondin expression. Thrombospondins are endogenous anti-angiogenic matricellular proteins known to regulate tumor growth and angiogenesis. We observed that both Tie-2 and subsequent PI3Kinase signaling regulates thrombospondin-1 expression. These data have lead to the model that Angiopoietin signaling through Tie-2 activates PI3Kinase/Akt, which represses thrombospondin expression. Thus, targeting Tie-2 with small molecules maybe efficacious as an anti-angiogenic therapy.