Epidemiological approaches to the study of cardiovascular malformations (CVMs) face challenges of disease definition, nomenclature, changing diagnostic methodologies, the rarity of the disease in the general population, and the incorporation of current knowledge on genetics and morphogenesis into designing studies to investigate risk factors and implement preventive strategies. Previous studies, especially the population-based Baltimore-Washington Infant Study, have documented variability in the prevalence of specific types of CVM by time, place, and personal characteristics and have highlighted the potential prevention of diabetes-associated heart malformations through timely medical management of pre-conception diabetes. Left-sided obstructive heart defects have been identified as targets for new studies of genetic risk factors. Potential environmental risk factors for CVMs also have been identified, such as organic solvents and pesticides, coincident with the emergence of new strategies to study genetic susceptibility and gene-environment interactions. Increased collaborative, multicenter research on these and other factors, such as nutritional factors in early pregnancy, offers new hope for potentially reducing the burden of CVM in the population.