Heme is an essential molecule for living aerobic organisms and is involved in a remarkable array of diverse biological processes. In the cardiovascular system, heme plays a major role in gas exchange, mitochondrial energy production, antioxidant defense, and signal transduction. Although heme, as the prosthetic group of hemoglobin, is most commonly associated with oxygen transport, heme is also required for the function of many cardiac enzymes, including mitochondrial electron transport chain complexes and heme-containing antioxidant proteins, such as peroxidase and catalase. Despite the vital role of heme in the cardiovascular system, this molecule remains understudied outside of the erythropoietic system. This review aims to summarize the important observations of heme in cardiovascular physiology and pathology.