Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in adolescence, and may lead to heart failure at any age. However, significant heterogeneity in the clinical course and phenotypic expression exists. Next to left ventricular hypertrophy, an impaired myocardial blood flow (MBF) during stress and inefficient cardiac metabolism are other characteristics of HCM. Studies using positron emission tomography (PET) have led to an enhanced understanding of the role that myocardial ischaemia and impaired energetics play in the clinical course of HCM. The blunted vasodilator reserve in the absence of an epicardial coronary stenosis is the result of microvascular dysfunction. Microvascular dysfunction, in turn, represents a predisposing factor for myocardial ischaemia, which may lead to cardiac dysfunction and fibrosis. Correspondingly, the severity of microvascular dysfunction has been shown to serve as a major predictor of mortality. Myocardial energetics in HCM has been studied with similar interest as mounting evidence suggests that mechano-energetic uncoupling may play a central role in its pathogenesis. Although prognostic data related to an impaired energetic state in HCM are lacking, it may hold prognostic relevance. Consequently, enhancing perfusion and restoring energetics have gained considerable attention as potential strategies to alter the natural course of HCM. In this regard, myocardial perfusion and metabolic imaging serves as a valuable tool to monitor the effects of therapeutic interventions on the pathophysiology of HCM.