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Normal cardiovascular development requires complex remodeling of the outflow tract and pharyngeal arch arteries to create the separate pulmonic and systemic circulations. During remodeling, the outflow tract is septated to form the ascending aorta and the pulmonary trunk. The initially symmetrical pharyngeal arch arteries are remodeled to form the aortic arch, subclavian and carotid arteries. Remodeling is mediated by a population of neural crest cells arising between the mid-otic placode and somite four called the cardiac neural crest. Cardiac neural crest cells form smooth muscle and pericytes in the great arteries, and the neurons of cardiac innervation. In addition to the physical contribution of smooth muscle to the cardiovascular system, cardiac neural crest cells also provide signals required for the maintenance and differentiation of the other cell layers in the pharyngeal apparatus. Reciprocal signaling between the cardiac neural crest cells and cardiogenic mesoderm of the secondary heart field is required for elaboration of the conotruncus and disruption in this signaling results in primary myocardial dysfunction. Cardiovascular defects attributed to the cardiac neural crest cells may reflect either cell autonomous defects in the neural crest or defects in signaling between the neural crest and adjacent cell layers.