One of the most critical times in the life of a protein is during its biogenesis at the ribosome. A nascent polypeptide cannot achieve its final fold while still bound to the ribosome, and is at risk of being accessed by the cellular quality control machinery. However, the extent to which cotranslational ubiquitination and degradation occur remains under debate. Conflicting reports exist, ranging from 40% of nascent chains being subject to cotranslational degradation to claims that nascent polypeptides are, on the contrary, protected from degradation. Here, we developed a direct and quantitative method to determine the extent of cotranslational ubiquitination using ribosome isolation coupled to ubiquitin-affinity purification. We find that cotranslational ubiquitination occurs at low levels, and that at least a fraction of ubiquitinated nascent chains is targeted to the proteasome for degradation. We determined which proteins are susceptible to cotranslational ubiquitination and find that intrinsic sequence features determine the cotranslational ubiquitination of a specific subset of proteins. These proteins are more aggregation-prone, highly expressed and longer than 400 amino acids. Short proteins seem to be protected from cotranslational ubiquitination. One such mechanism could be the cotranslational formation of folded structures, which lead us to disrupt cotranslational folding by deleting chaperones or through drugs such as azetidine-2-carboxylic acid (AZC). Both lead to an increase of cotranslational ubiquitination as observed by pulse-labeling as well as microarray analysis. Ribosome-associated chaperones and cotranslational folding seem to have evolved to prevent a high degree of nascent chain degradation/ubiquitination. Similarly to ribosome-associated chaperones, the ubiquitin-proteasome-system may also be able to access nascent protein chains, but rather target them for degradation. We therefore determined which parts of the UPS mediate cotranslational ubiquitination. A clear E2-E3 relationship could however not be established, possibly due to redundancy in the cellular ubiquitin ligase network. Finally, we find that disruption of mRNA quality control components also leads to enhanced ubiquitination of nascent chains, suggesting that cotranslational quality control serves to avoid the production of erroneous proteins and protect the cell from resulting toxicity.