Abstract: Total anomalous pulmonary venous connection (TAPVC) is a rare and serious congenital heartdisease, in which none of the pulmonary veins connect to the left atrium and instead directly connectto the right atrium or the systemic venous system. The growth and development of children with TAPVCis significantly limited. TAPVC-induced cyanosis and tissue hypoxia is gradually worsened after birth, which seriously threatens the life of those affected. TAPVC is an absolute indication for surgical repair. However, itscauses and mechanisms are still unclear. In recent years, the development of modern moleculargenetics has led to a preliminary understanding of the pathogenesis of TAPVC. This article reviews research progress in the pathogenesis of TAPVC and clinical implications.