Abstract-Significant advances in the understanding of the molecular and genetic basis of congenital heart disease have emerged from gene inactivation studies in mice and from human genetic investigations. However, the ability to utilize information gleaned from animal models to inform clinical care of patients depends on an accurate anatomic analysis and presentation in terms that are meaningful to the clinical pediatric cardiologist. Likewise, the enormous depth and breadth of accumulated clinical experience can inform the developmental biologist and can highlight the importance and interrelationships of particular phenotypes. The explosion of potentially informative genetic tools demands that basic scientists and clinicians concerned with congenital cardiac disease enhance the ongoing bidirectional dialogue. In some cases, categories of congenital disease familiar to clinicians are not recognized by developmental biologists, and mechanisms accepted by the biologist seem inconsistent with clinical experience. In this review, we summarize some of the more clinically significant forms of congenital heart disease, and we highlight relevant genetic and developmental pathways. Key Words: congenital heart disease Ⅲ developmental biology Ⅲ animal models C ongenital heart disease (CHD) affects over 1 out of every 100 live births 1,2 and is responsible for the vast majority of prenatal losses. Additionally, 3 per 1000 live births will require an intervention (either catheter-based or surgical) during the first year of life. Despite the importance of this devastating complex of diseases, the causes are largely unknown. What are the obstacles to unraveling the molecular controls of heart morphogenesis? A confluence of recent advances suggests that we are in the midst of a period of significant discovery that will reshape our understanding of congenital cardiac disorders. These advances include the description of an increasing number of gene-targeted mouse models of human cardiac disease, the availability of nearly complete genome sequence for multiple organisms, and increasingly sophisticated bioinformatics tools with which to utilize this data. In addition, the rapidly expanding single nucleotide polymorphism density map will soon make whole genome scans for the genetic causes of rare diseases more fruitful. Once specific causative genes are identified or implicated, the analysis of gene function and the mechanisms underlying the development of cardiovascular disorders can be analyzed in animal models. The manipulation of gene expression is now possible not only in mouse models, where homolo-