The burden of aortic stenosis is increasing steadily and, despite major advances in diagnosis and management, surgical valve replacement is still the only effective treatment. Most recently, experimental studies in animals and clinical studies in humans have shown that myocardial hypertrophy, microcirculatory dysfunction and cardiomyocyte apoptosis are among the central pathophysiologic mechanisms involved in the natural history of aortic stenosis, i.e. the passage from a compensated and hypertrophic heart to a dysfunctional heart prone to ischemia, arrhythmia and pump failure. This updated review emphasizes the promises of these new research avenues as well as their potential therapeutic applications.