Ubiquitination and deubiquitination are critical post-translational modifications that regulate protein stability and play essential roles in cancer development. The ubiquitin-proteasome system (UPS) is involved in various cancer hallmarks, including sustained proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genome instability and mutation, tumor-promoting inflammation, reprogramming energy metabolism, evading immune destruction, unlocking phenotypic plasticity, nonmutational epigenetic reprogramming, polymorphic microbiomes, and senescent cells. The UPS regulates the levels of proteins such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in the tumor microenvironment, enhancing immunotherapy effectiveness. Proteolysis targeting chimeras (PROTACs) and molecular glues are novel therapeutic approaches that target the UPS. Recent studies have shown that ubiquitination and deubiquitination regulate cancer progression through various mechanisms, including the regulation of signaling pathways such as EGFR, MAPK, and PI3K/AKT/mTOR. The E3 ligase TRIM28 and deubiquitinating enzymes such as USP22 and USP7 play important roles in regulating cancer cell proliferation and survival. The UPS also influences cell death processes such as apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis. Targeting the UPS offers promising therapeutic strategies for cancer treatment.Ubiquitination and deubiquitination are critical post-translational modifications that regulate protein stability and play essential roles in cancer development. The ubiquitin-proteasome system (UPS) is involved in various cancer hallmarks, including sustained proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genome instability and mutation, tumor-promoting inflammation, reprogramming energy metabolism, evading immune destruction, unlocking phenotypic plasticity, nonmutational epigenetic reprogramming, polymorphic microbiomes, and senescent cells. The UPS regulates the levels of proteins such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in the tumor microenvironment, enhancing immunotherapy effectiveness. Proteolysis targeting chimeras (PROTACs) and molecular glues are novel therapeutic approaches that target the UPS. Recent studies have shown that ubiquitination and deubiquitination regulate cancer progression through various mechanisms, including the regulation of signaling pathways such as EGFR, MAPK, and PI3K/AKT/mTOR. The E3 ligase TRIM28 and deubiquitinating enzymes such as USP22 and USP7 play important roles in regulating cancer cell proliferation and survival. The UPS also influences cell death processes such as apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis. Targeting the UPS offers promising therapeutic strategies for cancer treatment.