SIGNAL transducers and activators of transcription (Stats) are activated by tyrosine phosphorylation in response to cytokines, and are thought to mediate many of their functional responses^1–4. Stat6 is activated in response to interleukin (IL)-4 (refs 5,6) and may contribute to various functions including mitogenesis, T-helper cell differentiation and immunoglobulin i so type switching⁷. To evaluate the role of Stat6, we generated Stat6-null mice (Stat6^-l-) by gene disruption in embryonic stem cells. The mice were viable, indicating the lack of a non-redundant function in normal development. Although naive lymphoid cell development was normal, Stat6^-l- mice were deficient in IL-4-mediated functions including Th2 helper T-cell differentiation, expression of cell surface markers, and immunoglobulin class switching to IgE. In contrast, IL-4-mediated proliferation was only partly affected.