More children die from congenital heart disease (CHD) each year than are diagnosed with cancer. Although CHD is the most common human birth defect, the etiology of the vast majority of CHDs remains unknown. The difficulty in elucidating the molecular and genetic bases for CHD reflects the complex nature of this and other birth defects. Most CHD occurs sporadically, but the recurrence risk in subsequent pregnancies of parents with one affected child is ≈5%, or 5-fold higher than in other pregnancies. For some types of CHD, the recurrence risk can be as high as 10% to 15%.1 Thus, a genetic predisposition to CHD is likely present in affected individuals, but a second or third insult may occur during embryogenesis to contribute to the cardiac defects observed clinically. This possibility is similar to the multiple-hit theory in the pathogenesis of cancer and could come in the form of environmental or other genetic factors that accentuate effects of predisposing genetic mutations. Evidence for this theory in CHD comes from patients with similar genetic mutations who display widely varying forms of CHD or no CHD at all.2 3 This complexity and the often lethal nature of CHD have resulted in a paucity of large human families amenable to genetic linkage analysis,4 5 limiting the usefulness of classical genetic analyses. The study by Lee et al6 in this issue of Circulation Research provides evidence that a more systematic approach directed at identifying genes important in cardiac formation may yield insight into the bases of CHD. Lyons and his …