Hesr genes are members of the hairy and enhancer of split-related (hesr) gene family of basic helix-loop-helix-type transcriptional repressors. hesr genes have been implicated in cardiovascular development as the primary targets of Notch signaling. Functional analysis of hesr2 knockout mice revealed abnormal cardiac hemodynamics, such as atrioventricular valve regurgitation and reduced left ventricular systolic function, caused by hypoplastic AV valves and abnormal cardiomyocytes. Recent evidence demonstrates that hesr1 and hesr2 function redundantly in epithelial-to-mesenchymal transformation during atrioventricular valve formation and maintenance of trabecular cells in the heart ventricles, and in arterial-venous differentiation of blood vessels. This review highlights the many functions of the hesr gene family in heart and vessel development.