<p>UFMylation is a ubiquitin-like post-translational modification that has a central role in ribosome-associated quality control at the endoplasmic reticulum (ER-RQC). Through a dedicated enzymatic cascade, UFM1 is conjugated to select substrates, notably the 60S ribosomal subunit protein RPL26, to maintain endoplasmic reticulum and ribosomal integrity under cellular stress. This Review focuses on the structural and mechanistic basis of UFMylation in ER-RQC and its contribution to proteostasis. Although recent studies have identified a growing number of putative UFM1-modified proteins across diverse cellular pathways, the physiological importance of many of these substrates remains unclear. We highlight both the emerging functional breadth of UFMylation and the need for caution in interpreting substrate relevance. UFMylation is increasingly linked to disease, including neurodevelopmental disorders and cancer, underscoring its biological importance. Together, these findings position UFMylation as a key regulatory system connecting endoplasmic reticulum function to broader stress responses.</p>