Pediatric heart disease comprises many forms of cardiovascular disease in the young including cardiovascular malformations (CVM), cardiomyopathies, vasculopathies, e.g., Marfan syndrome, and cardiac arrhythmias. CVM are an important component of pediatric heart disease and constitute a major portion of clinically significant birth defects. In the past decade, the complementary nature of genetic, developmental, and biochemical approaches have contributed to extraordinary advances in understanding the origins of pediatric heart disease. Results of the studies of the cardiac transcription factor, NKX2.5, illustrate these accomplishments and at the same time provide a forecast of the nature of future genetic studies to better understand the origins of pediatric heart disease.