Netherton syndrome is a rare, autosomal recessive disorder that is characterized by congenital ichthyosis, trichorrhexis invaginata, and atopic diathesis. Ichthyosis presents at birth with erythroderma and subsequently evolves into ichthyosis linearis circumflexa; hair shaft abnormalities tend to present later. The disorder is caused by loss-of-function mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene that encodes LEKTI (lympho-epithelial Kazal-type related inhibitor), which is a protease inhibitor that counteracts epidermal proteases involved in desquamation. Use of topical medications is limited by potential for systemic absorption and toxicity in the setting of a defective skin barrier. Therapeutic options include topical glucocorticoids and retinoids, oral retinoids, and narrowband ultraviolet B phototherapy. Topical tacrolimus has been shown to be efficacious and may be used safely with careful laboratory monitoring.