Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease. In AD patients, the combination of a genetic predisposition for skin barrier dysfunction and dysfunctional innate and adaptive immune responses leads to a higher frequency of bacterial and viral skin infections. The innate immune system quickly mobilizes an unspecific, standardized first-line defense against different pathogens. Defects in this system lead to barrier dysfunction which results in increased protein allergen penetration through the epidermis and predisposes to secondary skin infections. Two loss-of-function mutations in the epidermal filaggrin gene are associated with AD. Also, inducible endogenous antibiotics such as the antimicrobial peptides cathelicidin and the beta-defensins may show defective function in lesional AD skin. Eczema herpeticum is a disseminated viral infection almost exclusively diagnosed in AD patients, which is based on unmasking of the viral entry receptor nectin-1, lack of cathelicidin production by keratinocytes, and depletion of Type I IFN-producing plasmacytoid dendritic cells from AD skin. Future therapeutic approaches to AD may include enhancement of impaired innate in addition to downregulation of dysfunctional adaptive immunity.