Immunoglobulin E (IgE) is a key mediator of anti-parasitic and anti-tumour immunity. However it is also a critical component of atopic and autoimmune diseases, and elevated serum IgE levels are a common indicator of immune dysregulation. In this review we survey the literature on genetic associations of elevated IgE in humans and mice. We find that defects in a limited number of pathways explain the majority of gene associations with IgE. Commonly, elevated IgE is associated with defects in Th bias and B cell class switching, severe T cell tolerance defects and defects in immunity at the host-environment interface. These genetic data demonstrate the mechanisms of control over IgE production and the manner in which they can be circumvented. (C) 2010 Elsevier Ltd. All rights reserved.