This review discusses the role of ubiquitination and deubiquitination in cancer, focusing on the mechanisms and therapeutic potential of the ubiquitin-proteasome system (UPS). Ubiquitination, a posttranslational modification, is crucial for regulating protein stability and is dysregulated in various cancers. The UPS, composed of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3), plays a central role in cancer by regulating multiple pathways, including metabolic reprogramming, immune evasion, and phenotypic plasticity. The review highlights the functions of different types of ubiquitination, such as monoubiquitination, linear ubiquitination, K48-linked polyubiquitination, and K63-linked polyubiquitination, and their roles in cancer hallmarks. It also explores novel therapeutic strategies, including proteolysis targeting chimeras (PROTACs) and molecular glues, which leverage the UPS to target and degrade specific proteins. The review further discusses the impact of ubiquitination and deubiquitination on key signaling pathways, such as EGFR, MAPK, PI3K/AKT/mTOR, and the regulation of tumor suppressors like p53 and RB. Additionally, it examines the role of ubiquitination in cell death processes, including apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis, and the potential of targeting these processes for cancer therapy. Finally, the review explores the UPS's role in enabling replicative immortality and inducing angiogenesis, providing insights into the complex mechanisms underlying cancer progression and suggesting novel therapeutic approaches.This review discusses the role of ubiquitination and deubiquitination in cancer, focusing on the mechanisms and therapeutic potential of the ubiquitin-proteasome system (UPS). Ubiquitination, a posttranslational modification, is crucial for regulating protein stability and is dysregulated in various cancers. The UPS, composed of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3), plays a central role in cancer by regulating multiple pathways, including metabolic reprogramming, immune evasion, and phenotypic plasticity. The review highlights the functions of different types of ubiquitination, such as monoubiquitination, linear ubiquitination, K48-linked polyubiquitination, and K63-linked polyubiquitination, and their roles in cancer hallmarks. It also explores novel therapeutic strategies, including proteolysis targeting chimeras (PROTACs) and molecular glues, which leverage the UPS to target and degrade specific proteins. The review further discusses the impact of ubiquitination and deubiquitination on key signaling pathways, such as EGFR, MAPK, PI3K/AKT/mTOR, and the regulation of tumor suppressors like p53 and RB. Additionally, it examines the role of ubiquitination in cell death processes, including apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis, and the potential of targeting these processes for cancer therapy. Finally, the review explores the UPS's role in enabling replicative immortality and inducing angiogenesis, providing insights into the complex mechanisms underlying cancer progression and suggesting novel therapeutic approaches.