Arrhythmogenic cardiomyopathy is characterized by a high incidence of ventricular tachyarrhythmias, which often occur early in the disease before significant ventricular remodeling or contractile dysfunction develops. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is the most common clinicopathological form of this group of diseases, but left ventricular and biventricular forms have been increasingly recognized. Approximately a third of patients with arrhythmogenic cardiomyopathy have mutations in genes encoding proteins of the desmosome, cell-to-cell adhesion organelles located at cardiac myocyte intercalated disks. Using immunohistochemistry in heart biopsies or autopsy specimens, we have observed diminished localization at intercalated disks of specific patterns of desmosomal proteins in a great majority of patients with ARVC. Because some of these proteins play roles as both structural proteins in cell-to-cell mechanical junctions and as signaling molecules, the pathogenesis of arrhythmogenic cardiomyopathy is probably related to both derangements in cell-to-cell adhesion and altered nuclear signaling. We have also observed diminished immunoreactive signal for the gap junction protein Cx43 at intercalated disks in virtually all patients with ARVC. Gap junction remodeling occurs diffusely in ARVC, and it appears early in the disease before significant degenerative changes of the myocardium have developed. Thus, mutations in desmosomal proteins may not only cause myocyte injury eventually leading to cell death and fibro-fatty tissue replacement but may also contribute to development of anatomic substrates of sudden death by remodeling gap junctions and altering electrical conduction.