Malformations of the cardiovascular system are the most frequently occurring type of birth defect, appearing in nearly one percent of newborn infants. The majority of congenital heart defects are due to abnormal development of the valves and membranous septa. 1 These tissues arise from mesenchymal outgrowths, referred to as the cardiac cushions, that develop within two regions of the tubular embryonic heart: the atrioventricular (AV) canal and the ventricular outflow tract (conotruncus). 2 The formation of the cushions within only these regions of the developing heart may be due to segmental patterning of the primitive heart tube. The cushions initially appear as regionally restricted thickenings of the cardiac jelly, the extracellular matrix (ECM) that resides between the myocardium and endocardium of the primitive heart tube. Cells migrate into the cushions as endothelial cells of the endocardium transform to mesenchyme. 2 With regard to the formation of the endocardium, there is evidence for dual cellular origins, both within and outside the heart-forming fields. 35 This may explain, at least in part, the heterogeneity of the endocardium; that is, some cells transform to mesenchyme, whereas other endothelial cells remain vascular. 4-67 Furthermore, those endocardia! and myocardial cells that arise from the heart-forming regions may share a common bipotential precursor. In this paper, we will give an overview of AV valvuloseptal morphogenesis (Fig 1) from the commitment of stem cells to this lineage during the onset of gastrulation, through the establishment of the AV cushions and their subsequent development into the valves and membranous septa. Moreover, we will present what is known about the molecular regulation of these developmental processes. It should be noted that the developmental biology of the outflow tract cushions contains many similarities to that of the AV canal. However, as the molecular biology of the AV cushions has been analyzed in much greater detail, we will emphasize AV cushion development in this review. Readers interested in biological details unique to the outflow tract region are encouraged to consult a recent review on outflow tract morphogenesis. 8