In early stage calcific aortic valve disease (CAVD), traditional cardiovascular risk factors promote valvular lesions via atherosclerosis-like mechanisms. Increased valvular oxidative injury causes transcriptional upregulation of the Wnt/β-catenin, Runx2/Cbfa1, and Msx2 pathways, promoting myofibroblast transdifferentiation into osteogenic phenotypes. Systemic and paracrine regulators of osteoblast function, calcium homeostasis, and dystrophic epitaxial calcification play an increasing role as calcification progresses. Genetic factors, valve morphology (e.g., bicuspid valves), and shear stress likely contribute to disease progression across the full spectrum of disease. MetS = metabolic syndrome; NOS = nitric oxide synthase.