Vascular smooth muscle cells (VSMC) situated in the tunica media of veins and arteries are central to maintaining conduit integrity in the face of mechanical forces inherent within the cardiovascular system. The predominant mechanical force influencing VSMC structural organisation and signalling is cyclic stretch. VSMC phenotype is manipulated by externally applied stretch which regulates the activity of their contractile apparatus. Stretch modulates cell shape, cytoplasmic organisation, and intracellular processes leading to migration, proliferation, or contraction. Drug therapy directed at the components of the signalling pathways influenced by stretch may ultimately prevent cardiovascular pathology such as myointimal hyperplasia.