Aortic valve disease is major contributor to mortality and morbidity in the US. The dominant manifestation of the disease is calcification of the leaflets that leads to stenosis or regurgitation, which contribute to heart disease and failure. Because open-chest valve replacement is undesirable, we have been working on pharmacological strategies to prevent or reverse valve calcification. In this talk, I will present our recent work that demonstrates the mechanical contributions that initiate calcific morphogenesis, the cell-cell interactions and intercellular mechanisms that are utilized, and old drug targets that can be used in a novel manner to prevent calcification. Our work is supported by the NIH, NSF, American Heart Association, and the Wallace H. Coulter Foundation.