The establishment and maintenance of cell and tissue polarity is crucial for a range of biological processes, such as oriented division, migration, adhesion and barrier function. The molecular pathways that regulate cell and tissue polarity have been extensively studied in lower organisms as well as in mammalian cell culture. By contrast, relatively little is still known about how polarization regulates the in vivo formation and homeostasis of mammalian tissues. Several recent papers have identified crucial roles for mammalian polarity proteins in a range of in vivo processes, including stem cell behavior, cell fate determination, junction formation and maintenance and organ development. Using the epidermis of the skin as a model system, this Commentary aims to discuss the in vivo significance of cell and tissue polarity in the regulation of mammalian tissue morphogenesis, homeostasis and disease. Specifically, we discuss the mechanisms by which the molecular players previously identified to determine polarity in vitro and/or in lower organisms regulate epidermal stratification; orient cell division to drive cell fate determination within the epidermal lineage; and orient hair follicles. We also describe how altered polarity signaling contributes to skin cancer.