In its function of separating pulmonary and systemic arterial blood flow, the ductus arteriosus, which connects both circuits, either closes permanently at a certain stage in development or attains a capacity to close and reopen depending on the physiological needs in certain species. In air-breathing vertebrates varying from lungfish to mammals, the ductus arteriosus derives from the sixth pharyngeal arch artery, and in preparation for its specific task, undergoes its own unique differentiation programme, starting early in development. To date, the mechanisms involved in defining this unique status, as compared to the other great arteries, are unclear. This review clarifies some of the elusiveness of the ductus arteriosus. It includes a comparative description of this artery in species exemplifying the different classes of air-breathing vertebrates, and illustrates similarities and differences in morphogenesis and closure mechanisms among the species. It also deals with possible influences of vascular innervation and with congenital anomalies in which the ductus arteriosus is involved. New data suggest that HOXB5 expression in the neural crest along the dorsal half of the sixth arch artery may be involved in the instigation of ductus arteriosus differentiation.