Arterial stiffness and wave reflection are fast emerging as therapeutic targets in their own right. While thiazide diuretics have little or no effect on either arterial stiffness or wave reflection, vasodilators including nitrates and phosphodiesterase type-5 inhibitors e.g., sildenafil, reduce wave reflections and aortic pressures but not aortic stiffness. ß-blockers have the opposite effect; they reduce aortic stiffness but increase aortic pulse pressure and wave reflections while calcium antagonists and α-blockers show varying effects on the vascular wall. Drugs targeting the renin–angiotensin–aldosterone system, namely angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs) and aldosterone antagonists have been shown as the most effective in reducing both arterial stiffness and wave reflection, and in some cases, to a greater extent than predicted from the extent of blood pressure (BP) reduction. Also, there is evidence of an additive effect on arterial stiffness with combined ACEI and ARBs. Exploring further the synergistic effects of anti-hypertensive drugs on arterial stiffness, a polypill containing a low-dose combination of a thiazide diuretic, calcium antagonist, ß-blocker and an ACEI, decreased arterial stiffness more than the individual drugs in standard doses. However, beyond the dynamic effects of anti-hypertensive drugs, future therapies may directly target vascular structural alterations including collagen degradation, advanced glycation end-products, the matrix metalloproteinases and vascular inflammation. Finally, one can speculate about the role of pharmacogenomics which may help tailor “de-stiffening therapy” in individuals with stiff arteries.