Calcific aortic stenosis and atherosclerosis have been investigated separately in experimental in vitro and in vivo studies and in clinical studies. The similarities identified in both diseases suggest that similar pathogenic pathways are involved in both conditions. Most current therapeutic studies are focused on statins. The evidence suggests that statin effects on valves may, in large part, be independent of the lipid lowering effects of the drug. There are several molecules that play significant regulatory roles on the development and progression of valve sclerosis and calcification and on growth and complications of atherosclerotic plaques. The purpose of this review is to discuss the pathogenic features of the two conditions, highlight the important similarities, and then review the data that suggest that transforming growth factor-beta may play a key regulatory role in both diseases and that this is worthy of study as a potential therapeutic target for both conditions.