Vascular Smooth Muscle Cells (VSMCs) are the stromal cells of the vascular wall, continually exposed to mechanical signals and biochemical components generated in the blood compartment. They are involved in all the physiological functions and the pathological changes responsible for arterial stiffening. Due to their contractile tonus, VSMCs of resistance vessels participate in the regulation of blood pressure and also in arterial stiffness. VSMCs of conduit arteries respond to hypertension-induced increases in wall stress by an increase in cell protein synthesis and extracellular matrix secretion. These responses are mediated by complex signaling pathways, mainly involving RhoA and extracellular signal-regulated kinase1/2. Serum response factor and miRNA expression represent main mechanisms controlling the pattern of gene expression. A progressive decrease in plasticity and reprogramming potential of VSMCs plays a complementary role contributing to the increase in arterial stiffness and associated cardiovascular risk factors in old humans. These key signaling pathways have become the focus of modern aging research and will undoubtedly provide a rich resource for the development of selective drugs interfering with either of these processes and prevention of the number one cause of death in the modern world.