T-cell dependent antibody responses require the coordinated activation and differentiation of antigen-specific B and T cells resulting in the production of high-affinity and neutralizing antigen-specific antibodies. Following interactions with specific antigen and the receipt of T cell help, activated B cells can undergo multiple fates including becoming short-lived plasmablasts or germinal center B cells which in turn can give rise to long-lived plasma cells or memory B cells which are critical for sustained humoral immunity. Many of the signals that control these fates are still poorly described. Autosomal dominant hyper IgE syndrome (AD-HIES) is a rare human primary immunodeficiency caused by heterozygous mutations in the gene encoding the transcription factor STAT3. Patients with AD-HIES suffer recurrent pneumonias and have decreased memory B cells and antigen-specific antibody responses suggesting a critical role for STAT3 in regulating antibody-mediated immunity. Consistent with this, STAT3 is involved in signaling pathways downstream of receptors for multiple cytokines including IL21, which has previously been implicated in regulating B cell differentiation. To determine the role of STAT3 in directing B cell responses in a dynamic in vivo and antigen-specific setting, we have used mice expressing a transgenic BCR specific for HEL combined with conditional deletion of Stat3 in B cells. These studies reveal that STAT3 signaling is a critical regulator of the expansion, differentiation, class switching and affinity maturation of B cells. Together these provide insight into the pathophysiology underlying the antibody-mediated defects observed in AD-HIES.