Keratinocytes are the major structural component of the epidermis. They differentiate from the basal through spinous to granular layers, and abrupt loss of nucleus pushes them to differentiate into cornified layers, which exfoliates as scales. Differentiation process is tightly controlled by the organized expression of transcription factors and other regulators, which sustains the physiological function of the skin barrier. The genetic abnormality of the molecules expressed in this pathway causes hereditary skin disorders and defects in barrier function. Ichthyosis is caused by keratins, enzymes, and structural proteins involved in lipid metabolism and cornified envelope formation. Atopic dermatitis seemed to be an immune-oriented disease, but the recent finding revealed filaggrin as a causative factor. Keratinocytes respond to acute injury by releasing alarmins. IL-33 is one of such alarmins, which provoke Th2-type inflammation. IL-33 works as a cytokine and, at the same time, as nuclear protein. IL-33 has double-faced nature, with pro- and anti-inflammatory functions. Epidermis, covering the entire body, should stay silent at minor insults, while it should provoke inflammatory signals at emergency. IL-33 and other double-faced molecules may play a role in fine tuning the complexed function of epidermal keratinocytes to maintain the homeostasis of human body.