Coronary atherosclerotic heart disease (CHD) is a common clinical chronic heart disease. Inflammation and immune response play pivotal roles in the development of atherosclerosis and ischemic myocardial diseases, and have become the focuses of cardiovascular disease research. Abnormal inflammatory immune response promotes atherogenesis and affects myocardial injury and tissue repair after acute myocardial infarction. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine generation. Histamine is a biogenic amine that has multiple functions through the activation of its widely distributed histamine receptors. Histamine regulates the differentiation and function of innate immune cells and adaptive immune cells. Recent studies have identified the new cellular source of histamine in immune cells and in ischemic myocardial injury. Targeting histamine and its downstream signaling molecules may provide new research strategies for the prevention and treatment of coronary heart disease.