By its strategic position at the interface between blood and tissues, endothelial cells control blood fluidity and continued tissue perfusion while simultaneously they direct inflammatory cells to areas in need of defense or repair. The endothelial response depends on specific tissue needs and adapts to local stresses. Endothelial cells counteract coagulation by providing tissue factor and thrombin inhibitors and receptors for protein C activation. The receptor PAR-1 is differentially activated by thrombin and the activated protein C/EPCR complex, resulting in antithrombotic and anti-inflammatory effects. Thrombin and vasoactive agents release von Willebrand factor as ultra-large platelet-binding multimers, which are cleaved by ADAMTS13. Platelets can also facilitate leukocyte-endothelium interaction. Platelet activation is prevented by nitric oxide, prostacyclin, and exonucleotidases. Thrombin-cleaved ADAMTS18 induces disintegration of platelet aggregates while tissue-type plasminogen activator initiates fibrinolysis. Fibrin and products of platelets and inflammatory cells modulate the angiogenic response of endothelial cells and contribute to tissue repair.