Signal transducer and activator of transcription (STAT) proteins are a group of transcription factors that transmit signals from the extracellular milieu of cells to the nucleus. They are crucial for the signaling of many cytokines that are mediators of allergic inflammation. Considerable information is known about the activation of STATs and their role in gene transcription; comparably much less is known about how STAT signaling is regulated. Because STATs are critical for the induction of many genes crucial for the allergic cascade and immune host defense, understanding the regulation of these molecules will provide novel insights into allergic and immunodeficiency disorders and will likely identify new targets for therapeutic interventions. This review will summarize the current understanding of the regulation of STAT signaling, emphasizing recent observations.