There is compelling evidence that prenatal exposures to environmental xenobiotics adversely affect human development and childhood. Among all birth defects, congenital heart disease (CHD) is the most prevalent of all congenital malformations and remains the leading cause of death. It has been estimated that in most cases the causes of heart defects remain unknown, while a growing number of studies have indicated the potential role of environmental agents as risk factors in CHD occurrence. In particular, maternal exposure to chemicals during the first trimester of pregnancy represents the most critical window of exposure for CHD. Specific classes of xenobiotics (e.g. organochlorine pesticides, organic solvents, air pollutants) have been identified as potential risk factors for CHD. Nonetheless, the knowledge gained is currently still incomplete as a consequence of the frequent heterogeneity of the methods applied and the difficulty in estimating the net effect of environmental pollution on the pregnant mother. The presence of multiple sources of pollution, both indoor and outdoor, together with individual lifestyle factors, may represent a further confounding element for association with the disease. A future new approach for research should probably focus on individual measurements of professional, domestic, and urban exposure to physical and chemical pollutants in order to accurately retrace the environmental exposure of parents of affected offspring during the pre-conceptional and pregnancy periods.