The lasting legacy of Donald McDonald has been in the establishment of physiological and biophysical principles of the relation of blood pressure and flow in arteries. This relation is determined by physical properties of arteries, among which wall stiffness is a dominant parameter. Increased arterial stiffness leads to an increase in pulse pressure due to alterations in the capacitive properties of large arteries and the increase in pulse wave velocity, which leads to early return of reflected waves. While the haemodynamic and biophysical effects of arterial stiffness have been studied extensively and are well established, the underlying mechanisms responsible for the alteration of the structural properties of the arterial wall are not as well understood. Some potential mechanisms will be addressed in relation to the interaction of the cellular and acellular components and their effect on the structural integrity of the arterial wall. The modification of the smooth muscle cell to influence medial calcification and the endothelium-dependent nitric oxide pathways affecting the extracellular matrix through post-translational modification of proteins form part of positive feedback mechanisms in the regulation of arterial stiffness through cellular and molecular processes. This is further modulated by neurogenic effects on smooth muscle contractility affecting wall stiffness. While the passive effects on the arterial wall due to blood pressure and heart rate cannot be readily modified, uncovering cellular, molecular and neurogenic mechanisms regulating arterial stiffness can offer novel means to interrogate pathways leading to the detrimental effects of degeneration of arterial function and altered relation of pressure and flow.