Hemodynamic forces associated with blood flow play a vital role in the endothelial regulation of vascular tone, remodeling and the initiation and progression of vascular diseases such as atherosclerosis and hypertension. Crucial elements in endothelium-mediated events within the blood vessel are bioactive peptide signals and their associated hydrolytic enzymes. This review examines the relationship between hemodynamic forces such as shear stress and cyclic strain, and an important group of peptide-degrading enzymes within the endothelium, the thermolysin-like zinc metallopeptidases.