"Experiments of nature" due to single gene mutations resulting in human immunodeficiency states have revealed critical roles for several genes in regulating lymphocyte development and the generation of protective immunity. Recently, heterozygous mutations in STAT3 were found to cause autosomal dominant hyper-IgE syndrome, a condition affecting not only the immune system but also other mesenchymal and ectodermal tissues, including bones, cranium, teeth, and skin. STAT proteins operate to integrate signals from surface receptors, including cytokine receptors, that regulate growth and differentiation of multiple cell lineages. In this article, we will review how the study of STAT3 deficiency in humans and mice has highlighted nonredundant roles of STAT3, and of specific cytokines, in diverse cellular processes such as antimicrobial immunity and protection at epithelial barriers, the generation of functional humoral immune responses, bone formation, and keratinocyte biology.