The heart develops from a simple left–right (L–R) symmetrical tube. Through a complex process of looping and remodelling, it becomes a highly L–R asymmetrical organ with distinct asymmetries in both morphology and function. Abnormal cardiac L–R patterning can result in a spectrum of defects that include, dextrocardia (a malposition of the heart to the right), isomerism of the atria (both atria being morphologically right-sided or left-sided), abnormal ventricular topology (e.g. the morphological left ventricle being dextral to the morphological right ventricle) or mirror-image topology (associated with situs inversus). Intermediate forms include abnormalities such as situs ambiguus and heterotaxia. L–R patterning abnormalities are typically associated with cardiac malformations, and it has become clear that an isolated septal, outflow tract and aortic arch malformation may be the only presenting manifestation of an L–R patterning defect. In the last two decades, there have been seminal advances in our understanding of the mechanisms controlling L–R patterning, and how mutations in L–R patterning genes result in human cardiac malformation. In this review, we provide an overview of the transcriptional mechanisms that result in asymmetric gene activation in mammals, how they receive information from signalling pathways, and how this translates to abnormal cardiac development.