Hypoxia-inducible factor (HIF) is a set of transcription factors that regulate the cellular response to hypoxia. There is a great body of evidence supporting the protective role of HIF-1α in cardiovascular pathophysiology, however, newer studies are hinting at a maladaptive and deleterious role of this transcription factor that merits further investigation. There is a general agreement, however, that HIF-mediated responses appear to differ under conditions of acute and chronic oxygen deprivation. The intensity and sustainability of HIF-1α activation are major determinants of whether the responses are pathological or beneficial. HIF activation is seen to be beneficial in the setting of acute myocardial ischemia and deleterious in chronic conditions. In this review, we will focus on recent insights into the role of HIF-1α in the heart and especially in the setting of ischemic heart disease.