In Western countries, calcific aortic valve stenosis (CAS) is widely common, representing the third cause of death among cardiovascular diseases (CVD). The burden of CAS is high, with an increasing prevalence rate related to age. An efficient medical treatment, according to guidelines, lacks to prevent the development and to reduce the progression of CAS. In this context, due to the aging population and the lack of effective medical management, the prevalence is expected to double-triple within the next decades. In our review, we aim to provide an overview of the underlying mechanisms of pathogenesis and the current state of the art regarding pathophysiological insights and novel potential therapeutic targets.