Desmosomes are morphologically and biochemically defined cell‐cell junctions that are required for maintaining the mechanical integrity of skin and the heart in adult mammals. Furthermore, since mice with null mutations in desmosomal plaque proteins (plakoglobin and desmoplakin) die in utero, it is also evident that desmosomes are indispensable for normal embryonic development. This review focuses on the role of desmosomes in vivo. We will summarize the effects of mutations in desmosomal genes on pre‐ and post‐embryonic development of mouse and man and discuss recent findings relating to the specific role of desmosomal cadherins in skin differentiation and homeostasis.