Interleukin (IL)-33 is a cytokine that is released from epithelial and endothelial cells at barrier surfaces upon tissue stress or damage to operate as an alarmin. IL-33 has been primarily implicated in the induction of T helper (Th) 2 type immune responses. Therefore, IL-33 has attracted a lot of interest as a potential therapeutic target in asthma and other allergic diseases. Over the years, it has become clear that IL-33 has a much broader activity and also contributes to Th1 immunity, expanding the possibilities for therapeutic modulation of IL-33 activity to multiple inflammatory diseases. However, more recently IL-33 has also been shown to mediate immunosuppression and tissue repair by activating regulatory T cells (Treg) and promoting M2 macrophage polarization. These pleiotropic activities of IL-33 illustrate the need for a tight molecular regulation of IL-33 activity, and have to be taken into account when IL-33 or its receptor is targeted for therapeutic modulation. Here we review the multiple molecular mechanisms that regulate IL-33 activity and describe how IL-33 can shape innate and adaptive immune responses by promoting Th1, Th2 and Treg function. Finally, we will discuss the possibilities for therapeutic modulation of IL-33 signaling as well as possible safety issues.