Asymmetric cell divisions promote stratification and differentiation of mammalian skin. The epidermis, a stratified squamous epithelium, forms a barrier against harmful microbes and retains body fluids. Basal cells in the epidermis periodically detach from the basement membrane, move outward, and eventually die. Once suprabasal, cells stop dividing and enter a differentiation program. The mechanism of stratification is poorly understood, but studies suggest that stratification occurs through delamination and movement of epidermal cells. However, most culture conditions favor keratinocytes that lack the polarity and cuboidal morphology of basal keratinocytes in tissue. An alternative mechanism is that stratification occurs through asymmetric cell divisions, where the mitotic spindle orients perpendicularly to the basement membrane. The study shows that basal epidermal cells divide asymmetrically, generating a committed suprabasal cell and a proliferative basal cell. Integrins and cadherins are essential for the apical localization of atypical protein kinase C, the Par3–LGN–Inscuteable complex, and NuMA–dynactin to align the spindle. The study found that in embryonic development, a few mitotic cells divide perpendicularly to the basement membrane, as judged by staining with DAPI and anti-tubulin. Closer inspection revealed the presence of some suprabasal cells within the single-layered epithelium. In later stages of development, the epidermis becomes multi-layered, and more than 70% of spindles are oriented perpendicularly to the basement membrane. Perpendicular divisions yield one basal and one suprabasal cell, and their temporal appearance during skin development correlates well with stratification. A functional link was provided by examining p63-null embryos, which are defective in the transcription factor p63 but also in stratification. Divisions in p63-null epidermis were lateral to the basement membrane. In normal adults, homeostasis of stratification also seemed to be dependent on perpendicular divisions, as most divisions in both adult epidermis and tongue occurred in this fashion. The study also found that the population of basal cells increased threefold between E13.5 and E15.5, reflecting the increasing size of the embryo and the ability of basal cells to divide symmetrically and remain attached to the basement membrane. The increase in suprabasal cells during this time was much too large to be explained by the concomitant increase in asymmetric cell divisions. This conundrum was solved by discovering that, in contrast to fully stratified E18.5 and postnatal epidermis, many E15.5 suprabasal cells were proliferative. The study also found that the apical localization of LGN, mInsc, and Par3 is essential for asymmetric cell divisions. The localization of these proteins is dependent on integrins and cell-cell adhesionAsymmetric cell divisions promote stratification and differentiation of mammalian skin. The epidermis, a stratified squamous epithelium, forms a barrier against harmful microbes and retains body fluids. Basal cells in the epidermis periodically detach from the basement membrane, move outward, and eventually die. Once suprabasal, cells stop dividing and enter a differentiation program. The mechanism of stratification is poorly understood, but studies suggest that stratification occurs through delamination and movement of epidermal cells. However, most culture conditions favor keratinocytes that lack the polarity and cuboidal morphology of basal keratinocytes in tissue. An alternative mechanism is that stratification occurs through asymmetric cell divisions, where the mitotic spindle orients perpendicularly to the basement membrane. The study shows that basal epidermal cells divide asymmetrically, generating a committed suprabasal cell and a proliferative basal cell. Integrins and cadherins are essential for the apical localization of atypical protein kinase C, the Par3–LGN–Inscuteable complex, and NuMA–dynactin to align the spindle. The study found that in embryonic development, a few mitotic cells divide perpendicularly to the basement membrane, as judged by staining with DAPI and anti-tubulin. Closer inspection revealed the presence of some suprabasal cells within the single-layered epithelium. In later stages of development, the epidermis becomes multi-layered, and more than 70% of spindles are oriented perpendicularly to the basement membrane. Perpendicular divisions yield one basal and one suprabasal cell, and their temporal appearance during skin development correlates well with stratification. A functional link was provided by examining p63-null embryos, which are defective in the transcription factor p63 but also in stratification. Divisions in p63-null epidermis were lateral to the basement membrane. In normal adults, homeostasis of stratification also seemed to be dependent on perpendicular divisions, as most divisions in both adult epidermis and tongue occurred in this fashion. The study also found that the population of basal cells increased threefold between E13.5 and E15.5, reflecting the increasing size of the embryo and the ability of basal cells to divide symmetrically and remain attached to the basement membrane. The increase in suprabasal cells during this time was much too large to be explained by the concomitant increase in asymmetric cell divisions. This conundrum was solved by discovering that, in contrast to fully stratified E18.5 and postnatal epidermis, many E15.5 suprabasal cells were proliferative. The study also found that the apical localization of LGN, mInsc, and Par3 is essential for asymmetric cell divisions. The localization of these proteins is dependent on integrins and cell-cell adhesion