Congenital heart disease (CHD) remains a leading cause of morbidity and mortality in childhood and is the most common human birth defect, affecting nearly 1% of all live births worldwide. The morphogenetic events that are disrupted during cardiogenesis that lead to CHD are now partially understood, as are many of the molecular networks that guide normal heart development. Studies of rare Mendelian forms of familial CHD, as well as CHD associated with stereotypic syndromes, have revealed numerous single-gene mutations that cause CHD. However, mutations in these genes are infrequent in the more common sporadic form of CHD. Despite epidemiological evidence for an inherited component in sporadic CHD, the contribution of inherited variants or de novo mutations in the setting of CHD has been unclear. A recent landmark article in Nature begins to tackle this question by using modern genetic approaches and suggests that roughly 10% of sporadic CHD cases have de novo mutations that contribute significantly to the disease process.