Cardiovascular disease (CVD) accounts for the largest number of deaths worldwide, necessitating the development of novel treatments and prevention strategies. Given the huge energy demands placed on the heart, it is not surprising that changes in energy metabolism play a key role in the development of cardiac dysfunction in CVD. A reduction in oxygen delivery to the heart, hypoxia, is sensed and responded to by the hypoxia-inducible factor (HIF) and its family of proteins, by regulating the oxygen-dependent signalling cascade and subsequent response. Hypoxia is one of the main drivers of metabolic change in ischaemic disease and myocardial infarction, and we therefore suggest that HIF may be an attractive therapeutic target. In this review, we assess cardiac energy metabolism in health and disease, and how these can be regulated by HIF-1α activation. We then present an overview of research in the field of hypoxia-mimetic drugs recently developed in other treatment fields, which provide insight into the potential of systemic HIF-1α activation therapy for treating the heart.