Purpose of reviewThe endothelial cell plasma membrane is a metabolically active, dynamic, and fluid microenvironment where pericellular proteolysis plays a critical role. Membrane-anchored proteases may be expressed by endothelial cells as well as mural cells and leukocytes with distribution both inside and outside of the vascular system. Here, we will review the recent advances in our understanding of the direct and indirect roles of membrane-anchored proteases in vascular biology and the possible conservation of their extravascular functions in endothelial cell biology.Recent findingsMembrane-anchored proteases belonging to the serine or metalloprotease families contain amino-terminal or carboxy-terminal domains, which serve to tether their extracellular protease domains directly at the plasma membrane. This architecture enables protease function and substrate repertoire to be regulated through dynamic localization in distinct areas of the cell membrane. These proteases are proving to be key components of the cell machinery for regulating vascular permeability, generation of vasoactive peptides, receptor tyrosine kinase transactivation, extracellular matrix proteolysis, and angiogenesis.SummaryA complex picture of the interdependence between membrane-anchored protease localization and function is emerging that may provide a mechanism for precise coordination of extracellular signals and intracellular responses through communication with the cytoskeleton and with cellular signaling molecules.