The STAT family proteins provide critical signals for immune cell development, differentiation, and proinflammatory and anti-inflammatory responses. Inborn errors of immunity (IEIs) are caused by single gene defects leading to immune deficiency and/or dysregulation, and they have provided opportunities to identify genes important for regulating the human immune response. Studies of patients with IEIs due to altered STAT signaling, and mouse models of these diseases, have helped to shape current understanding of the mechanisms whereby STAT signaling and protein interactions regulate immunity. Although many STAT signaling pathways are shared, clinical and immune phenotypes in patients with monogenic defects of STAT signaling highlight both redundant and nonredundant pathways. In this review, we provide an overview of the shared and unique signaling pathways used by STATs, phenotypes of IEIs with altered STAT signaling, and recent discoveries that have provided insight into the human immune response and treatment of disease.