Mechanotransduction has a key role in vascular development, physiology, and disease states. Piezo1 is a mechanosensitive (MS) nonselective cationic channel that occurs in endothelial and vascular smooth muscle cells. It is activated by shear stress associated with increases in local blood flow, as well as by cell membrane stretch upon elevation of blood pressure. Here, we briefly review the pharmacological modulators of Piezo and discuss current understanding of the role of Piezo1 in vascular mechanobiology and associated clinical disorders, such as atherosclerosis and hypertension. Ultimately, we believe that this research will help identify novel therapeutic strategies for the treatment of vascular diseases.