Left-right asymmetric looping of the cardiac tube during embryogenesis places the segments of the cardiac tube that give rise to the left and right chambers into their appropriate spatial orientation. Cardiac looping is required for subsequent formation of septa, valves, and outflow tract. Defects in embryonic left-right axis formation represent a significant portion of congenital heart malformations. Recent discoveries make it apparent that the orientation of cardiac tube looping is dependent on a cascade of genes in noncardiac embryonic cells, including lateral cells and midline cells, before neural tube closure. These observations suggest a linkage between complex cardiac defects and subtle midline defects in early embryos.