Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder characterized by the early occurrence of serious tachyarrhythmias often out of proportion to the extent of structural changes and contractile derangement. Approximately 40% of patients with ARVC have one or more mutations in genes encoding proteins in desmosomes, intercellular adhesion junctions which, in cardiac myocytes, reside within intercalated disks. Some desmosomal proteins fulfill roles both as structural proteins in cell-cell adhesion junctions and as nuclear signaling molecules. It has been proposed that mutations in desmosomal proteins implicated in ARVC may perturb the normal balance of protein in junctions and the cytosol which, in turn, could promote dysregulated gene expression circumventing the normal controls of Wnt signaling pathways. This review highlights recent advances in understanding the pathogenesis of ARVC and presents evidence, suggesting that the disease is caused by a combination of altered cellular biomechanical behavior and altered signaling.