Desmosomes are prominent adhesion sites that are tightly associated with the cytoplasmic intermediate filament cytoskeleton providing mechanical stability in epithelia and also in several nonepithelial tissues such as cardiac muscle and meninges. They are unique in terms of ultrastructural appearance and molecular composition with cell type-specific variations. The dynamic assembly properties of desmosomes are important prerequisites for the acquisition and maintenance of tissue homeostasis. Disturbance of this equilibrium therefore not only compromises mechanical resilience but also affects many other tissue functions as becomes evident in various experimental scenarios and multiple diseases.