Identification of a memory drug target ISRIB is a potent inhibitor of the integrated stress response (ISR), which involves the activation of eIF2α-specific kinases, phosphorylation of eIF2α, and consequent down-regulation of global translation levels. ISRIB is also a candidate drug for treating certain memory disorders. ISRIB does not prevent eIF2α phosphorylation and must therefore act downstream of this step. Sekine et al. now report that ISRIB reverses the inhibitory effect of eIF2α phosphorylation on the activity of eIF2B, a dedicated guanine nucleotide exchange factor, enhancing its activity independently of phosphorylation (see the Perspective by Hinnebusch). The authors isolated ISRIB-resistant cells and identified a genetic lesion in a short N-terminal region of eIF2Bδ that appears to be responsible for the observed phenotype. Science , this issue p. 1027 ; see also p. 967