Protein post‑translational modifications (PTMs) play crucial roles in various life activities and aberrant protein modifications are closely associated with numerous major human diseases. Ubiquitination, the first identified protein modification system, involves the covalent attachment of ubiquitin molecules to lysine residues of target proteins. UFMylation, a recently discovered ubiquitin‑like modification, shares similarities with ubiquitination. The precursor form of ubiquitin fold modifier 1 (UFM1) undergoes synthesis and cleavage by UFM1‑specific protease 1 or UFM1‑specific protease 2 to generate activated UFM1‑G83. Subsequently, UFM1‑G83 is activated by a specific E1‑like activase, UFM1‑activating enzyme 5. UFM1‑conjugating enzyme 1 and an E3‑like ligase, UFM1‑specific ligase 1, recognize the target protein and facilitate UFMylation, leading to the degradation of the target protein. Current knowledge regarding UFMylation remains limited. Previous studies have demonstrated that defects in the UFMylation pathway can result in embryonic lethality in mice and various human diseases, highlighting the critical biological functions of UFMylation. However, the precise mechanisms underlying UFMylation remain elusive. This present review aimed to summarize recent research advances in UFMylation, with the aim of providing novel insights and perspectives for future investigations into this essential protein modification system.