Cardiovascular development has become a crucial element of transgene technology in that many transgenic and knockout mice unexpectedly present with a cardiac phenotype, which often turns out to be embryolethal. This demonstrates that formation of the heart and the connecting vessels is essential for the functioning vertebrate organism. The embryonic mesoderm is the source of both the cardiogenic plate, giving rise to the future myocardium as well as the endocardium that will line the system on the inner side. Genetic cascades are unravelled that direct dextral looping and subsequent secondary looping and wedging of the outflow tract of the primitive heart tube. This tube consists of a number of transitional zones and intervening primitive cardiac chambers. After septation and valve formation, the mature two atria and two ventricles still contain elements of the primitive chambers as well as transitional zones. An essential additional element is the contribution of extracardiac cell populations like neural crest cells and epicardium-derived cells. Whereas the neural crest cell is of specific importance for outflow tract septation and formation of the pharyngeal arch arteries, the epicardium-derived cells are essential for proper maturation of the myocardium and coronary vascular formation. Inductive signals, sometimes linked to apoptosis, of the extracardiac cells are thought to be instructive for differentiation of the conduction system. In summary, cardiovascular development is a complex interplay of many cell-cell and cell-matrix interactions. Study of both (transgenic) animal models and human pathology is unravelling the mechanisms underlying congenital cardiac anomalies.