INTERFERONS (IFNs) α/β (type I) and γ (type II) bind to distinct cell surface receptors1, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention2,3. Previous studies using cell lines selected for their inability to respond to IFN-α (ref. 4) have shown that the protein kinase Tyk2 plays a central role in the IFN α/β response5. Here we report the isolation of the cell line γl A, selected for its inability to express IFN-γ-inducible cell-surface markers, that is deficient in all aspects of the IFN-γ response tested, but responds normally to IFNs α and β. The mutant cells can be complemented by the expression of another member of the JAK family of protein tyro-sine kinases, JAK2 (refs 6-9). Unlike IFNs α and β, IFN-γ induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine kinase activity. These responses are absent in γl A cells. JAK2 is therefore required for the response to IFN-γ but not to IFNs α and β.