Human heterotaxy syndrome is characterized by a wide variety of cardiac and extracardiac congenital malformations that are primarily induced by disorders of the left-right axis determination during early embryonic development. The cellular and molecular mechanisms of the left-right asymmetry have been extensively investigated in the past decade and the developmental mechanisms of the syndrome have been considerably elucidated. Medical and surgical management and treatment of heterotaxy syndrome have advanced as well. However, prognosis of the disease still remains unsatisfactory because the syndrome is often associated with a combination of complicated congenital heart diseases. Management of heterotaxy patients, particularly those who have undergone the Fontan procedure, is now one of the most important issues in pediatric and adult congenital heart disease clinics. In this review, we focus on the recent advances in knowledge of the genetic and molecular pathogenesis of heterotaxy syndrome, as well as its clinical features, management, and prognosis.