Cardiovascular malformations affect about 1% of newborns, yet much remains to be learned about the pathogenesis of these defects. Advances in understanding some of the molecular events involved in regulating cardiac morphogenesis are providing a new perspective with which to approach complex issues and questions related to congenital heart disease. More important, this new information provides not only unique opportunities for developing specific experimental models of congenital heart disease through direct genetic manipulation but also the basis for developing ways of therapeutically manipulating cardiac gene expression for some form of heart disease. This review presents recent advances in the understanding of the molecular aspects of cardiac development and how this information can be used to manipulate cardiac gene expression during development.