Ubiquitin is the small regulatory protein that tags other proteins for degradation by the proteasome. This process, known as ubiquitination or ubiquitylation, involves the covalent attachment of ubiquitin to lysine residues on target proteins through a series of enzymatic reactions involving E1 (activating), E2 (conjugating), and E3 (ligating) enzymes. Once polyubiquitin chains are formed on the target protein, they serve as a degradation signal recognised by the 26S proteasome. This mechanism is crucial for cellular protein homeostasis, cell cycle regulation, and signal transduction. The clinical relevance is highlighted by drugs like bortezomib, which inhibits the proteasome and prevents the degradation of pro-apoptotic proteins, leading to cancer cell death. Understanding this pathway is essential as dysregulation of the ubiquitin-proteasome system is implicated in various diseases including cancer, neurodegeneration, and autoimmune conditions.