The state of the lipid layer of the epidermis largely determines the functional ability of the epidermal barrier. Large-scale genome studies of patients with psoriasis showed a defect in several genes responsible for the formation of the epidermal barrier, among them a gene cluster of β-diphenzine, of late keratinizing membrane, and corneodesmosin. The content of ceramides, the main fraction of the lipid layer, which accounts for 50%, is significantly reduced in the psoriatic epidermis. Most likely, this is due to a decrease in their synthesis. Since the analysis of the level of enzymes providing processing of ceramides showed a significant decrease in the activity of serine-palmitoyltransferase, which catalyzes the synthesis of ceramides de novo, with the preserved activity of the enzymes that destroy them. A decrease in the level of ceramides leads to an increase in transepidermal fluid loss and to a decrease in the water-holding ability of the epidermis in psoriatic plaque compared to unchanged skin. The inverse relationship between the level of ceramides and the serine-palmitoyltransferase enzyme with PASI for mild and moderate psoriasis was shown. This fact indicates the relationship of the content of this lipid fraction in the epidermis with the severity of the disease. A low level of ceramides also negatively affects the activity of apoptotic signaling molecules, in particular protein kinase C-alpha, which disrupts the signal transduction pathways during apoptosis and contributes to enhanced keratinocyte proliferation. Topical glucocorticosteroids, widely used in the treatment of psoriasis, influence the content of ceramides in the epidermis and the state of the epidermal barrier. They inhibit the synthesis of ceramides, thereby enhancing initially disturbed processes. The inclusion of lipid-reducing topical drags with a high content of ceramides in the complex therapy of psoriasis is becoming relevant.