Atopic dermatitis (AD) is the most common polyetiologic inflammatory skin disease in industrialized countries. Recent non-clinical and clinical studies highlighted the crucial pathogenetic role of a damaged skin barrier in patients with AD. A crucial role in the skin barrier physiology is played by the protein filaggrin, which in addition to humectant function, controls structural protein aggregation, skin pH, antimicrobial peptides production by keratinocytes, photoprotection, and epidermal lipid synthesis. Mutations in the human filaggrin gene (FLG), which encodes filaggrin, are the most significant in AD development. The major determinant of filaggrin expression is the FLG genotype, which has three variants: null mutation, heterozygous variant, and absence of mutations in FLG in both alleles. Additional genetic (including intragenic copy number variation) and environmental modifiers can alter the filaggrin protein expression. Transcutaneous penetration of irritants and allergens leads to chronic inflammation and contributes to the atopic march development. In addition, persistent skin inflammation further weakens the skin barrier function, resulting in a «vicious circle» of pathogenetic interactions between the altered skin barrier and the immune system: Th2 response causes downregulation of filaggrin irrespective of FLG mutation status and significantly aggravates the course of AD. Understanding of skin barrier physiology is important for effective AD therapy and prevention of subsequent atopic manifestations. Currently, the most promising methods of restoring the skin barrier in at-risk individuals are therapies that enhance filaggrin production.