The recent discovery that collision of ribosomes triggers quality control and stress responses in eukaryotes has shifted the perspective of the field. Collided eukaryotic ribosomes adopt a unique structure, acting as a ubiquitin signaling platform for various response factors. While several of the signals that determine which downstream pathways are activated have been uncovered, we are only beginning to learn how the specificity for the activation of each process is achieved during collisions. This review will summarize those findings and how ribosome-associated factors act as molecular sentinels, linking aberrations in translation to the overall cellular state. Insights into how cells respond to ribosome collision events will provide greater understanding of the role of the ribosome in the maintenance of cellular homeostasis.