Heart development and the establishment of a functional circulatory circuit are complex biological processes in which subtle perturbations may result in catastrophic consequences of cardiovascular birth defects. Studies in model organisms, most notably the mouse and the zebrafish, have identified genes that also cause these life-threatening defects when mutated in humans. Gradually, a framework for the genetic pathway controlling these events is now beginning to emerge. However, the puzzling phenotypic variability of the cardiovascular disease phenotype in humans and the recent identification of phenotypic modifiers using model organisms indicates that other genetic loci might interact to modify the disease phenotype. To illustrate this, we review the role of vascular endothelial growth factor (VEGF) during vascular and cardiac development and stress how zebrafish and mouse genetic studies have helped us to understand the role this growth factor has in human disease, in particular in the Di-George syndrome.