In HSV-1 (herpes simplex virus 1)-infected cells, the UL41 gene product carried with the virion has been shown to mediate the degradation of mRNA, leading to the shut-off of cellular protein synthesis. Analysis of the RNAs accumulating in cells infected with HSV-1 revealed the accumulation of RNAs encoding numerous cellular proteins both associated with and independent of activation of the NF-κB (nuclear factor κB) pathway. Studies on the activation of NF-κB and the expression and fate of selected cellular transcripts revealed the following. (i) In HSV-1-infected cells, NF-κB is activated by activated protein kinase R. Furthermore, the blockade of NF-κB translocation by suppression of protein kinase R activation does not render the cell more susceptible to apoptosis induced by viral gene expression. (ii) A number of mRNA up-regulated in infected cells [e.g. IκBα (inhibitory κBα), the immediate-early response protein IEX-1 and c-fos] are partially degraded and not translated. The degradation is UL41-dependent and results in deadenylation, endonucleolytic cleavage and 3′–5′ degradation. The 5′-portion resulting from the endonucleolytic cleavage tends to linger in the infected cells. To date, the RNAs processed in this manner contained ARE (AU-rich elements) in their 3′-untranslated domains. RNAs lacking ARE were expressed and not degraded in this manner. (iii) Tristetraprolin and T-cell internal antigen-1, cellular proteins involved in the degradation of ARE-containing RNAs, are induced and activated in infected cells and tristetraprolin interacts physically with the UL41 protein.