Atopic dermatitis (AD) is a highly pruritic, chronic, multifactorial skin disease predisposing to bacterial and viral infections based on abnormalities of the innate and acquired immune system. The innate system quickly mobilizes an inflexible, standardized first-line response against different pathogens. Epidermal barrier dysfunction 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. Langerhans cells and inflammatory dendritic epidermal cells (IDEC) express high affinity IgE receptors, which are functional in IgE-mediated antigen presentation. Inducible antimicrobial peptides including the antiviral cathelicidin and the antibacterial beta-defensins show defective upregulation in lesional AD skin. The desmosomal protein nectin-1 is unmasked in AD lesions, thus becoming a relevant herpes simplex virus (HSV) entry receptor. Type I IFN-producing plasmacytoid dendritic cells are decreased and dysfunctional in AD skin, predisposing the patients to viral skin infections. Molluscum contagiosum virus produces a unique IL-18 binding protein to evade antiviral defense mechanisms. Innate and adaptive immunity do not simply coexist but are linked to one another in a complex network of skin immunobiology.