IgE antibody plays an important role in allergic diseases. IgE synthesis by B cells requires two signals. The first signal is delivered by the cytokines IL-4 or IL-13, which target the Cepsilon gene for switch recombination. The second signal is delivered by interaction of the B cell surface antigen CD40 with its ligand (CD40L) expressed on activated T cells. This activates deletional switch recombination. We review the molecular mechanisms of IL-4 and CD40 signaling that lead to IgE isotype switching and discuss the implications for intervening to abort or suppress the IgE antibody response.