Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder that associates with nucleotide sequence variants in genes encoding sarcomere related proteins, and is recognized as the most common heritable cardiac diseases. Clinically, HCM can be extremely variable and this makes the diagnosis difficult until the development of serious or fatal events. Nevertheless, the main hallmark of HCM is represented by left ventricle hypertrophy that can be occasionally associated to cardiac arrhythmias, chest pain, diastolic dysfunction, obstruction of left ventricular outflow tract. The present review aims to focus on the complex interplay existing between the multifaceted non-genetic molecular mechanisms underlying HCM onset and progression, and the key pathophysiological role of abnormal coronary artery function. As the clinical course of HCM shows a mortality rate per year up to 6% the importance of innovative therapeutic strategies will be discussed, especially in regard to the use of potential endogenous coronary modulators to be enrolled as modifiers of HCM phenotype.