Abstract: Congenital heart diseases (CHD) are the most common birth defects worldwide. The etiology of CHD is multifactorial and intricate. Cardiac transcription factors, developmental genes and key molecules of signaling pathways required for early cardiac morphogenesis have been extensively studied in human CHD. Due to the complex etiology, the causes for most of the CHD cases are far from known. A better knowledge of the molecular mechanisms of CHD would enable us to improve intervening strategies and treatment. This review discusses the current progress in the study of the genetics, epigenetic mechanisms, and maternal nutrition underlying CHD, as well as their potential interactions. Besides, we also review the current in vivo/vitro genetic CHD models that can be used for better understanding of the molecular basis underlying CHD, hoping to provide novel therapeutic strategies for clinic treatment.