Desmosomes are highly organized intercellular junctions that provide mechanical integrity to tissues by anchoring intermediate filaments to sites of strong adhesion. Transcriptional regulation of desmosomal cadherins specifies their expression pattern and assembly into junctions of distinct composition, thus tailoring desmosome functions in adhesion and morphogenesis within different cells and complex tissues. Desmosome assembly and disassembly are regulated post-translationally by calcium, kinase/phosphatase activity, proteolytic processing, and cross talk with adherens junctions. Post-translational events also govern the level of non-junctional forms of plakoglobin and plakophilins. These armadillo proteins participate in various nuclear functions, in some cases transducing signals regulating cell growth and differentiation.