Angiopoietin-2 (ANG2), a ligand of the TIE2 receptor, modulates endothelial cell biology and destabilizes blood vessels to facilitate angiogenesis. Recent reports have shown that ANG2 inhibition, for example, by monoclonal antibodies, peptibodies, or CovX-Bodies, may achieve substantial antiangiogenic and antitumor responses in a variety of mouse tumor models, including spontaneous MMTV-PyMT mammary and RIP1-Tag2 pancreatic islet adenocarcinomas. There is also evidence that targeting the ANG2/TIE2 signaling pathway may inhibit the functions of TIE2-expressing macrophages (TEM), a tumor-associated macrophage subset endowed with proangiogenic activity in mouse tumor models. The clinical opportunities afforded by simultaneously targeting the effects of ANG2 on tumor angiogenesis and the proangiogenic activity of TEMs are discussed.