Post-translational modifications are at the apex of cellular communication and eventually regulate every aspect of life. The identification of new post-translational modifiers is opening alternative avenues in understanding fundamental cell biology processes and may ultimately provide novel therapeutic opportunities. The ubiquitin-fold modifier 1 (UFM1) is a post-translational modifier discovered a decade ago but its biological significance has remained mostly unknown. The field has recently witnessed an explosion of research uncovering the implications of the pathway to cellular homeostasis in living organisms. We overview recent advances in the function and regulation of the UFM1 pathway, and its implications for cell physiology and disease. The known functions of the UFM1 pathway mostly encompass the control of the proteostasis network, highlighting the involvement of the endoplasmic reticulum stress response known as the unfolded protein response.Recent discoveries have revealed unexpected roles for the UFM1 pathway in DNA damage response, ribosome biology, autophagy, gene expression control, and cell differentiation.The recent discovery of UFM1 conjugation to ribosomal protein RPL26 represents a unique way for cells with high secretory activity to tune ribosome turnover.Study of preclinical models of multiple diseases (liver, brain, intestine, and heart injury) has identified UFM1 conjugation as an important protective pathway.Genetic alterations to the UFM1 pathway are linked to human diseases affecting the nervous system.