The skin is the largest barrier organ of the human body and serves to protect the internal structure of the body from the harmful environment. The epidermis forms the outermost layer and is exposed to the environment. Keratinocytes are important constituent cells of the epidermis and alter their morphology and structural integrity through a highly complex differentiation process referred to as cornification. Abnormalities in the process of epidermal cornification can lead to skin barrier dysfunction. The epidermal differentiation complex (EDC) is a gene cluster located within a 2 Mb region of human chromosome 1q21. EDC is responsible for epithelial tissue development and for properties of the stratum corneum. One of the most important features of psoriasis is the abnormal terminal differentiation of keratinocytes. However, the relationship between EDC and the occurrence of psoriasis is still unclear. In this review, we summarize current knowledge regarding the physiological functions of EDC and discuss its possible contributions to the pathogenesis of psoriasis.