The reagenic antibody in the sera of atopic individuals, first described by Prausnitz and Kustner and later determined to be Immunoglobulin (Ig) E by the Ishizakas, plays a critical role in the pathogenesis of allergic disease. Investigation into the cellular basis of IgE regulation has provided important insights into a disease process that affects up to 30% of the population world-wide. Over the last decade, the molecular events regulating IgE synthesis have been actively investigated. In this review, we will discuss the various components of this system including the cells, cytokines, signal transduction events, and molecular mechanisms that participate in human IgE synthesis and explore rational therapeutic approaches directed at the modulation of these systems.