Since a constant supply of oxygen is essential to sustain life, organisms have evolved multiple defence mechanisms to ensure maintenance of the delicate balance between oxygen supply and demand. However, this homeostatic balance is perturbed in response to a severe impairment of oxygen supply, thereby activating maladaptive signalling cascades that result in cardiac damage. Past research efforts have largely focused on determining the pathophysiological effects of severe lack of oxygen. By contrast, and as reviewed here, exposure to moderate chronic hypoxia may induce cardioprotective properties. The hypothesis put forward is that chronic hypoxia triggers regulatory pathways that mediate long-term cardiac metabolic remodelling, particularly at the transcriptional level. The novel proposal is that exposure to chronic hypoxia triggers (a) oxygen-sensitive transcriptional modulators that induce a switch to increased carbohydrate metabolism (fetal gene programme) and (b) enhanced mitochondrial respiratory capacity to sustain and increase efficiency of mitochondrial energy production. These compensatory protective mechanisms preserve contractile function despite hypoxia.