The desmosomal cadherins (DCs) are adhesion molecules of desmosomes, intercellular junctions of epithelia and cardiac muscle. DCs have the unique ability to adopt a hyperadhesive state that is characterised by enhanced stability and adhesive strength. Hyperadhesion is important in embryonic development and wound healing, and DC expression is tightly regulated at the transcriptional and posttranslational levels. Desmosomes act as signalling centres and DCs have been linked to an array of intracellular signal transduction pathways that control cell proliferation and differentiation. DCs are targets of autoantibodies, bacterial toxins and mutations, resulting in skin blistering disease, cardiomyopathy and sometimes both. Here we consider the structure and function of the desmosomal cadherins, and their role in normal tissue biology and human disease.