Around 20% of all children worldwide suffer from Atopic Dermatitis (AD). Therefore, eczematous skin lesions and elevated serum Immunglobulin E (IgE) levels are common findings. Inborn Errors of Immunity (IEI) may be missed in the context of AD, and management and prognosis of these conditions can be substantially different. Children suffering from IEIs such as Hyper-IgE-Syndromes (HIES), Wiskott-Aldrich-syndrome (WAS), Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, Omenn syndrome, the atypical complete DiGeorge syndrome and skin barrier disorders like Comèl-Netherton-syndrome and Severe-dermatitis-multiple-allergies-and-metabolic-wasting (SAM) syndrome may present with additional “red flags”, which should raise a clinical suspicion for an underlying IEI. These “red flags” may include eczematous skin lesion manifesting prior to two month of life, disseminated or recurrent viral, bacterial or fungal infections, mucocutaneous candidiasis, purpura, chronic diarrhea, or abnormalities in development or of connective tissue. A differential blood count, as well as a lymphocyte subset analysis, total immunoglobulin levels and vaccination titers can help the clinician to decide whether a patient with eczematous skin lesions and elevated serum IgE should be referred to a clinical immunologist for a full immunologic work-up and broad genetic analysis.