Sepsis is a systemic inflammatory response to infection. A common end-feature, these patients regularly suffer from is the so-called multiple organ dysfunction syndrome, an often fatal consequence of organ hypoperfusion, coagulopathy, immune dysregulation,and mitochondrial dysfunction. Microvascular dysfunction critically contributes to the morbidity and mortality of this disease. The angiopoietin (Angpt)/Tie2 system consists of the transmembrane endothelial tyrosine kinase Tie2 and its circulating ligands (Angpt-1,-2, and -3/4). The balance between the canonical agonist Angpt-1 and its competitive inhibitor, Angpt-2, regulates basal endothelial barrier function and the leakage and vascular inflammation that develop in response to pathogens and cytokines. Here we summarize recent work in mice and men to highlight the therapeutic potential in this pathway to prevent or even reverse microvascular dysfunction in this deadly disease.