Identification of the molecular targets for post-translational modifications is an important step for explaining the regulated pathways. The ubiquitin-like molecule NEDD8 is implicated in the regulation of cell proliferation, viability and development. By combining proteomics and in vivo NEDDylation assays, we identified a subset of ribosomal proteins as novel targets for the NEDD8 pathway. We further show that the lack of NEDDylation in cells causes ribosomal protein instability. Our studies identify a novel and specific role of the NEDD8 pathway in protecting a subset of ribosomal proteins from destabilization.