Advances in our understanding of desmosomal diseases have provided a clear demonstration of the key role played by desmosomes in tissue and organ physiology, highlighting the importance of their dynamic and finely regulated structure. In this context, non‐desmosomal regulatory molecules have acquired increasing relevance in the study of this organelle resulting in extending the desmosomal interactome, named the “desmo‐adhesome.” Spatiotemporal changes in the expression and regulation of the desmo‐adhesome underlie a number of genetic, infectious, autoimmune, and malignant conditions. The aim of the present article was to examine the structural and functional relationship of the desmosome, by providing a comprehensive, yet focused overview of the constituents targeted in human disease. The inclusion of the novel regulatory network in the desmo‐adhesome pathophysiology opens new avenues to a deeper understanding of desmosomal diseases, potentially unveiling pathogenic mechanisms waiting to be explored. J. Cell. Physiol. 232: 496–505, 2017. © 2016 Wiley Periodicals, Inc. The desmosome has been the subject of intense research over the last 20 years. While several reviews have recently been published on this topic, none has investigated the desmosomal interactome as a whole. This review is unique in that it not only takes into account the diseases that are linked to primary desmosomal components but, also, includes the potential role of accessory molecules in epithelial disease and cancer.