Significance: Translation is an essential cellular process, and diverse signaling pathways have evolved to deal with problems arising during translation. Erroneous stalls and unresolved ribosome collisions are implicated in many pathologies, including neurodegeneration and metabolic dysregulation. Recent Advances: Many proteins involved in detection and clearance of stalled and collided ribosomes have been identified and studied in detail. Ribosome profiling techniques have revealed extensive and nonprogrammed ribosome stalling and leaky translation into the 3' untranslated regions of mRNAs. Impairment of protein synthesis has been linked to aging in yeast and mice. Critical Issues: Ribosomes act as sensors of cellular states, but the molecular mechanisms, as well as physiological relevance, remain understudied. Most of our current knowledge stems from work in yeast and simple multicellular organisms such as Caenorhabditis elegans, while we are only beginning to comprehend the role of ribosome surveillance in higher organisms. As an example, the ribotoxic stress response, a pathway responding to global translational stress, has been studied mostly in response to small translation inhibitors and ribotoxins, and has only recently been explored in physiological settings. This review focuses on ribosome-surveillance pathways and their importance for cell and tissue homeostasis upon naturally occurring insults such as oxidative stress, nutrient deprivation, and viral infections. Future Directions: A better insight into the physiological roles of ribosome-surveillance pathways and their crosstalk could lead to an improved understanding of human pathologies and aging. Antioxid. Redox Signal. 39, 336-350.