Abstract
The desmosome is a cell-cell adhesive junction that provides integrity and mechanical resistance to tissues through its attachment to the intermediate filament cytoskeleton. Defects in desmosomes cause diseases impacting the heart, epidermis, and other epithelia. In this review, we provide a historical perspective on the discovery of the desmosome and how the evolution of cellular imaging technologies revealed insights into desmosome structure and function. We also discuss recent findings using contemporary imaging approaches that have informed the molecular order, three-dimensional architecture, and associations of desmosomes with organelles such as the endoplasmic reticulum. Finally, we provide an updated model of desmosome molecular organization and speculate upon novel functions of this cell junction as a signaling center for sensing mechanical and other forms of cell stress.