Normal left-right asymmetry is highly conserved among vertebrates. Errors in the proper patterning of this axis are believed to lead to congenital anomalies of the heart and abdominal viscera, often with profound clinical consequences. We review briefly the nature of potential signals and signaling sources that lead to the break in left-right symmetry. The evidence suggests that left-right reversal, or homogenization, of these signals may lead to different consequences, and we explain some malpositions and malalignments of the atria, ventricles, and/or outflow tract that are seen in a variety of congenital cardiac diseases. We speculate that there are units of organ assembly responsive to laterality signals, and these units may be driven independently. One crucial source of signals appears to be the notochord and floorplate. In order to examine the clinical relationship of these midline structures to putative disorders of laterality, we review all patients with disturbances of normal laterality seen at the Massachusetts General Hospital over the past 20 years. We find a significant association between laterality defects and anomalies of the spine and other midline structures. Dev. Genet.