Here, we report on the antiviral properties of the newly generated Ifit2 2/2 mice; these mice, but not Ifit1 2/2 mice, were highly susceptible to neuropathogenesis after intranasal infection with vesicular stomatitis virus (VSV), a negative sense, singlestranded RNA rhabdovirus. VSV replication is highly sensitive to the inhibitory action of IFN and is routinely used to assay the antiviral activity of IFN in vitro [21] . As expected, IFNAR 2/2 mice are highly susceptible to VSV pathogenesis and the same is true for mice that specifically lack expression of IFNAR on the cells of their central nervous system (CNS) [1] . In spite of these observations, little is known about how IFN inhibits VSV replication in vivo. Our new results indicate that in the brain, but not in other organs, Ifit2 is a major mediator of IFN's protective effect against VSV. In contrast, Ifit2 could not protect mice from neuropathogenesis caused by encephalomyocarditis virus (EMCV), a picornavirus. Thus, we have uncovered a virusspecific, tissue-specific and ISG-specific antiviral effect of the IFN system.