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Atopic dermatitis (AD) and asthma are characterized by IgE-mediated atopic (allergic) responses to common proteins (allergens), many of which are proteinases. Loci influencing atopy have been localized to a number of chromosomal regions 1, including the chromosome 5q31 cytokine cluster 2, 3, 4. Netherton disease is a rare recessive skin disorder in which atopy is a universal accompaniment 5. The gene underlying Netherton disease (SPINK5) 6 encodes a 15-domain serine proteinase inhibitor (LEKTI) which is expressed in epithelial and mucosal surfaces and in the thymus 6, 7. We have identified six coding polymorphisms in SPINK5 (Table 1) and found that a Glu420→ Lys variant shows significant association with atopy and AD in two independent panels of families. Our results implicate a previously unrecognized pathway for the development of common allergic illnesses.