Terminally stalled ribosomes can initiate degradation of nascent polypeptides and the dissociation of ribosome subunits, a process known as ribosome-associated quality control (RQC). Using a reporter that quantitatively measures ribosome terminal stalling, Juszkiewicz and Hegde found that most ribosomes in human cells stalled when they encountered an array of 21 AAA Lys codons (AAA21) and that degradation of the 'arrested' nascent polypeptides was mediated by RQC. Depletion of the putative ubiquitin E3 ligase ZNF598 abolished terminal stalling at the AAA21 region. Moreover, ZNF598-mediated ubiquitylation of several ribosomal proteins, primarily 40S ribosomal protein S10, was necessary for RQC activation. Because translation of only poly(A) sequences that are longer than endogenous sequences can effectively trigger RQC, this mechanism could be tuned to prevent translation of the poly(A) tail.