Although impressive progress has been made in the diagnosis and treatment of congenital heart disease, there has been an explosion of new information about the basic molecular mechanisms that control normal heart development and subsequent congenital cardiovascular malformations. Since the advent of targeted null mutations in mice (gene "knockouts"), it has become increasingly evident that defects in the heart and vascular system frequently result from gene alterations and that these defects are often responsible for in utero demise. New genes have been discovered that control looping of the heart, distinguish arteries from veins, and direct formation of the semilunar valve and atrioventricular valves. A pivotal role for several genes expressed by the cardiac neural crest document the importance of these cells in aortic arch selection, in addition to their role in aorticopulmonary septation. In addition, myocardial and endothelial progenitor cells have been isolated from bone marrow stromal cells, and human embryonic stem cells have been successfully isolated, paving the way for developmental approaches to tissue engineering and organ regeneration. Finally, the first successful attempt at in utero manipulation of genes that might palliate certain forms of congenital heart disease has been presented. These recent advances are detailed in this article.