The epidermis contains epithelial cells, immune cells, and microbes which provides a physical and functional barrier to the protection of human skin. It plays critical roles in preventing environmental allergen penetration into the human body and responsing to microbial pathogens. Atopic dermatitis (AD) is the most common, complex chronic inflammatory skin disease. Skin barrier dysfunction is the initial step in the development of AD. Multiple factors, including immune dysregulation, filaggrin mutations, deficiency of antimicrobial peptides, and skin dysbiosis contribute to skin barrier defects. In the initial phase of AD, treatment with moisturizers improves skin barrier function and prevents the development of AD. With the progression of AD, effective topical and systemic therapies are needed to reduce immune pathway activation and general inflammation. Targeted microbiome therapy is also being developed to correct skin dysbiosis associated with AD. Improved identification and characterization of AD phenotypes and endotypes are required to optimize the precision medicine approach to AD.