Intermediate filament (IF) proteins are encoded by a ≥70 member gene family, the members of which are expressed in tissue-restricted and differentiation-specific patterns. The keratin family of IF proteins form the major cytoskeleton of all epithelia from heterodimers of type I and Type II keratin proteins. By interacting with desmosomes and hemidesmosomes, they contribute to tissue cohesion and protect epithelial tissues against various stresses. By virtue of additional protein interactions, keratins may integrate mechanical and chemical signaling processes and thereby tune cell responses to extracellular cues in distinct ways. Understanding corresponding molecular mechanisms will provide an understanding of disorders caused by mutations in ≥20 keratin genes and provide the basis for therapy development. During my presentation, I will briefly review keratin assembly and network organization. Next, I will discuss recent data on the role of keratins in desmosome formation and maintenance. Further, I will present preliminary transcriptome data from normal and keratin-deficient keratinocytes exposed to cyclic stretch, which reveal distinct changes in gene expression patterns. Finally, I will discuss potential therapy approaches to improve conditions of blistering keratin disorders, based on recent insights into posttranslational modifications.