SIGNAL transducers and activators of transcription (STATs) are activated by tyrosine phosphorylation in response to cytokines and mediate many of their functional responses^1–3. Stat4 was initially cloned as a result of its homology with Statl (refs 4, 5) and is widely expressed, although it is only tyrosine-phosphorylated after stimulation of T cells with interleukin (IL)-12 (refs 6, 7). IL-12 is required for the T-cell-independent induction of the cytokine interferon (IFN)-γ, a key step in the initial suppression of bacterial and parasitic infections. IL-12 is also important for the development of a Thl response, which is critical for effective host defence against intracellular pathogens^8,9. To determine the function of Stat4 and its role in IL-12 signalling, we have produced mice that lack Stat4 by gene targeting. The mice were viable and fertile, with no detectable defects in haemato-poiesis. However, all IL-12 functions tested were disrupted, including the induction of IFN-γ, mitogenesis, enhancement of natural killer cytolytic function and Thl differentiation.