IgE antibodies play a central role in the pathogenesis of atopic diseases and in host immunity against parasitic infections. IgE has potent activities on mast cells and basophils. IgE class switching is a very tightly controlled process, and serum IgE levels are very low compared with other immunoglobulin isotypes. Transcription factors that activate or inhibit the IgE gene promoter, as well as T(H)1 and T(H)2 cytokines are important in the regulation of IgE levels. Hyper-IgE syndrome; Wiskott-Aldrich syndrome; immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX); Omenn syndrome; and atypical complete DiGeorge syndrome are primary immune deficiencies that are associated with elevated serum IgE levels. Increased IgE levels in IPEX, Wiskott-Aldrich syndrome and Omenn syndrome are likely related to increased T(H)2 cytokine production caused by decreased a number or function of CD4(+)CD25(+)forkhead box protein P3(+) regulatory T cells. The link between signal transducer and activator of transcription 3 mutations and elevated serum IgE levels in hyper-IgE syndrome is unclear. Insight into IgE regulation provided by the study of primary immune deficiencies with elevated IgE has important implications for allergic diseases.