This review focuses on the role of sphingosine-1-phosphate (S1P) signaling in the heart, with particular emphasis on how it could be modulated therapeutically in the context of myocardial infarction (MI). After a brief general description of sphingolipid metabolism and signaling, this review will examine the relationship between S1P and the beneficial effects of high-density lipoprotein (HDL), and finally focus on the known actions of S1P on different mechanisms relevant to MI pathophysiology (cardiomyocyte protection, fibrosis, remodeling, arrhythmia, control of vascular tone and potential repair mechanisms). The potential of particular enzyme isoforms or receptor subtypes for the development of therapeutic agents for MI will also be explored.