Cardiac desmosomes form intercellular junctions at the boundaries of intercalated discs between neighboring cardiomyocytes and are essential for proper cell-to-cell coupling between cardiomyocytes and for normal mechanical and electrical function of myocardial tissue. Genetic mutations in desmosomal proteins have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), a clinically and genetically heterogeneous cardiac inherited disorder. The disease is characterized by progressive replacement of cardiomyocytes by fibrofatty tissue, ultimately resulting in ventricular dilation, cardiac dysfunction, and the occurrence of life-threatening arrhythmias. Despite increasing knowledge on the genetic basis of ARVC, the etiopathogenesis of the disease remains less understood. The recent development of a number of transgenic mouse models with either heterozygous knock-out of desmosomal proteins or overexpression of aberrant desmosomal components has provided novel insight into the potential mechanisms and final common pathways involved in ARVC. The various disease mechanisms are likely not mutually exclusive and may each contribute to the pathogenesis of ARVC. However, their applicability in the diverse genetic forms of the disease remains uncertain, and may only be ascertained by careful investigation of sequential histopathological and (sub)cellular changes occurring over time during the disease process. Insight into the etiopathogenesis of ARVC will be crucial for the future development of new therapies aimed at delaying onset or progression of this disease.