In eukaryotes, selective derepression of mRNA translation through altered utilization of upstream open reading frames (uORFs) or internal ribosomal entry sites (IRES) regulatory motifs following exposure to stress is regulated at the initiation stage through the increased phosphorylation of the eukaryotic initiation factor 2 on its subunit (eIF2). While there is only one known eIF2 kinase in yeast, general control nonderepressible 2 (GCN2), mammals have evolved to express at least four: GCN2, heme-regulated inhibitor kinase (HRI), double-stranded RNA-activated protein kinase (PKR) and PKR-like ER-resident kinase (PERK). So far, the main known distinction among these four kinases is their activation in response to different acute stressors. In the present study, we used the in situ perfused mouse liver model and hybridization array analyses to assess the general translational response to stress regulated by two of these kinases, GCN2 and PERK, and to differentiate between the downstream effects of activating GCN2 versus PERK. The resulting data showed that at least 2.5% of mouse liver mRNAs are subject to derepressed translation following stress. In addition, the data demonstrated that the eIF2 kinases, GCN2 and PERK, differentially regulate mRNA transcription and translation, which in the latter case suggests that increased eIF2 phosphorylation is not sufficient for derepression of translation. These findings open an avenue for more focused future research towards groups of mRNAs that code for the early cellular stress response proteins.