γ-Interferon (IFNγ) is generally thought to act by binding to cell surface receptors coupled to JAK-family kinases; these then phosphorylate STAT transcription factors, causing them to translocate to the nucleus. Things might not be so simple though: IFNγ can be endocytosed, and there is some evidence that intracellular IFNγ has biological effects and can even enter the nucleus. To examine the intracellular roles of IFNγ,Iqbal Ahmed and co-workers have generated mutants that lack a secretory signal and/or a nuclear localization signal (NLS) they have identified in the protein(see p. 3089). They find that the nonsecreted form has biological activities similar to those of wild-type (extracellular) IFNγ, including antiviral effects and upregulation of MHC class I molecules - if the NLS mutation is absent,however, nonsecreted IFNγ is inactive. The authors go on to demonstrate that intracellular IFNγ translocates to the nucleus as part of a complex containing its receptor (IFNGR1), STAT1α and an importin - again this requires the IFNγ NLS. They then show that extracellular IFNγundergoes receptor-mediated endocytosis and has NLS-dependent signalling activity, thus providing good evidence that nuclear translocation of wild-type IFNγ has a physiological role.