The receptor tyrosine kinase Tie2 is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance. The ligands for Tie2 are the angiopoietins, of which angiopoietin-1 and angiopoietin-2 have been the most studied. Angiopoietin-1 has been characterized as the primary activating ligand for Tie2 whereas the role of angiopoietin-2 remains controversial; activating Tie2 in some studies and inhibiting Tie2 in others. Our studies were aimed at understanding the regulation of Tie2 in endothelial cells by angiopoietin-1 and angiopoietin-2 and revealed that both ligands activated Tie2 in a concentration-dependent manner. Angiopoietin-2 was considerably weaker at activating Tie2 compared with angiopoietin-1 suggesting that angiopoietin-2 may be a partial agonist. Activation of Tie2 by these ligands resulted in differential turnover of the receptor where binding of angiopoietin-1, and to a lesser extent angiopoietin-2, induced rapid internalization and degradation of Tie2. Furthermore, our binding studies demonstrate that both ligands are differentially released from the endothelial cell surface after receptor activation and accumulate in the surrounding medium. Altogether, these data begin our understanding of the regulation of Tie2 and the activity of the angiopoietins after engaging the endothelial cell surface.