The congenital cardiac anomaly known as tetralogy of Fallot (TOF) is characterized by right ventricular outflow tract obstruction caused by subpulmonary stenosis, dextroposition (overriding) of the aorta, a ventricular septal defect, and right ventricular hypertrophy. The right ventricular hypertrophy is secondary to the presence of right ventricular outflow obstruction (pulmonic valvar or subvalvar stenosis or in the most severe case, atresia). Cyanosis in these patients is attributable to the passage of systemic venous blood into the aorta, bypassing the lungs, with the degree of cyanosis dependent on the severity of the outflow tract obstruction. The malformations that are classified as persistent truncus arteriosus (PTA) are characterized by a single multicuspid semilunar valve with a single vessel, the truncus, arising from the ventricles and giving rise to systemic, pulmonary, and coronary circulations. Thus, both PTA and TOF with pulmonary atresia are characterized by a single vessel emanating from the heart. In PTA, the septation that would divide the common arterial trunk into an aorta and pulmonary trunk is missing, whereas in TOF with pulmonary atresia, it is unclear whether this septation is missing or misplaced. Diagnosis of TOF with pulmonary atresia relies on the presence of a pulmonary valve remnant by clinical imaging. This criterion permits differentiation of TOF with pulmonary atresia and PTA. However, if the pulmonary atresia develops embryonically before a valve is formed, then this criterion would not distinguish PTA from TOF with pulmonary atresia. New findings in experimental mouse models by Théveniau-Ruissy et al reported recently in Circulation Research shed unexpected light on the embryogenesis of these defects and may allow differentiation of the 2 defects in ways that have not been used previously. 1