Abstract Protein biosynthesis is by far the most energy-consuming process during cellular proliferation; translation accounts for roughly 50% of the energy consumption in growing bacterial, and 30% in differentiating mammalian cells. At the heart of this essential process is the ribosome, the complex molecular machine that catalyzes the peptide bond formation. Therefore, to ensure continuous protein production, cells need to monitor the integrity of their ribosomes. Indeed, throughout the lifetime of the ribosome, its many components are subject to both mechanical and chemical assaults and the accumulated damage can render the ribosome translation-incompetent. At organismal level, alterations in ribosome structure and function have been associated diseases such as neurodegeneration, cancer and ribosomopathies. Although maintaining functional translation apparatus is essential for cell survival, the factors involved in the detection and degradation of faulty ribosomes remain poorly characterized. Studying ribosome surveillance has been hindered by a lack of robust methods for monitoring, purifying, and perturbing specific populations of ribosomes. This proposal aims at exploiting the recent advances in quantitative mass spectrometry, functional genomics methods, and genome editing to identify the factors necessary for coping with 1) defective intermediates during ribosome biogenesis, 2) damaged ribosomes, and 3) specialized ribosomes that have fulfilled their role. This work will advance our knowledge of a fundamental biological process, and improve our understanding of the molecular basis of complex human disease.