Ribosome-associated quality control (RQC) pathways protect cells from toxicity caused by incomplete protein products resulting from translation of damaged or problematic mRNAs. Extensive work in yeast has identified highly conserved mechanisms that lead to degradation of faulty mRNA and partially synthesized polypeptides. Here we used CRISPR-Cas9-based screening to search for additional RQC strategies in mammals. We found that failed translation leads to specific inhibition of translation initiation on that message. This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP. Model substrates and growth-based assays established that inhibition of additional rounds of translation acts in concert with known RQC pathways to prevent buildup of toxic proteins. Inability to block translation of faulty mRNAs and subsequent accumulation of partially synthesized polypeptides could explain the neurodevelopmental and neuropsychiatric disorders observed in mice and humans with compromised GIGYF2 function. Display omitted •Genome-wide CRISPRi screen identifies GIGYF2 and 4EHP as RQC factors•GIGYF2 and 4EHP work in parallel to nascent polypeptide degradation•GIGYF2 and 4EHP block translation initiation on faulty mRNAs•Translation inhibition prevents buildup of toxic, partially synthesized polypeptides Without a clearance mechanism, defective messages can trap translating ribosomes and result in toxic protein accumulation. Hickey et al. identified two factors that engage stalled ribosomes and block new rounds of translation on faulty messages. These and other quality control factors act in concert to prevent buildup of toxic proteins.