Cell–cell connectivity is an absolute requirement for the correct functioning of cells, tissues and entire organisms. At the level of the individual cell, direct cell–cell adherence and communication is mediated by the intercellular junction complexes: desmosomes, adherens, tight and gap junctions. A broad spectrum of inherited, infectious and auto‐immune diseases can affect the proper function of intercellular junctions and result in either diseases affecting specific individual tissues or widespread syndromic conditions. A particularly diverse group of diseases result from direct or indirect disruption of desmosomes—a consequence of their importance in tissue integrity, their extensive distribution, complex structure, and the wide variety of functions their components accomplish. As a consequence, disruption of desmosomal assembly, structure or integrity disrupts not only their intercellular adhesive function but also their functions in cell communication and regulation, leading to such diverse pathologies as cardiomyopathy, epidermal and mucosal blistering, palmoplantar keratoderma, woolly hair, keratosis, epidermolysis bullosa, ectodermal dysplasia and alopecia. Here, as well as describing the importance of the other intercellular junctions, we focus primarily on the desmosome, its structure and its role in disease. We will examine the various pathologies that result from impairment of desmosome function and thereby demonstrate the importance of desmosomes to tissues and to the organism as a whole. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.