IL-18, originally termed as interferon gamma (IFN-gamma) inducing factor, is a proinflammatory cytokine that belongs to the IL-1 cytokine superfamily. IL-18 plays an important role in immune, infectious, and inflammatory diseases due to its induction of IFN-gamma. However, accumulated evidence has demonstrated that other effects of IL-18 are independent of IFN-gamma. Here, we reviewed the current literatures regarding the role of IL-18 in the heart and cardiovascular system. Infiltrated neutrophils, resident macrophages, endothelial cells, smooth muscle cells, and cardiomyocytes in the heart are able to produce IL-18 in response to injury. IL-18 is produced as a biologically inactive precursor (pro-IL-18) that is activated by caspase 1 (the IL-1beta converting enzyme). Elevated IL-18 levels have been observed in cardiac tissue and circulation after myocardial I/R and sepsis. The possible cellular and molecular mechanisms concerning IL-18-induced myocardial injury include induction of inflammation, increased apoptosis, a cardiac hypertrophy effect, modulation of mitogen activated protein kinase activation, and changes in intracellular calcium. Finally, we briefly reviewed the therapeutic strategies for inhibiting IL-18's biological activity to protect cardiac tissue from injury.