The article discusses the evolving understanding of ubiquitin, a small protein that plays a crucial role in various cellular processes beyond protein degradation. Initially discovered in 1975, ubiquitin was found to be involved in protein degradation through the K48-linked polyubiquitin chain. However, recent studies have revealed that ubiquitin also participates in non-degradative functions, such as DNA repair, transcription regulation, and innate immunity. The discovery of non-canonical ubiquitin linkages, such as K63, has expanded the "ubiquitin code," revealing diverse biological roles. The K63-linked polyubiquitin chain is involved in DNA repair and gene silencing, while other linkages, like K6, K11, and K33, have been identified. The structural basis of K63 polyubiquitin chain assembly was elucidated through crystallographic studies, revealing the role of Mms2 in positioning the ubiquitin acceptor towards the active site of Ubc13. Histone ubiquitination has also been shown to play a role in transcription and the DNA damage response. For example, the ubiquitination of H2A-K119 is necessary for gene silencing, and the ubiquitination of H2A-K15 serves as a marker for DNA damage repair. Other histone ubiquitination marks, such as H2B-K120, are involved in transcription activation by promoting histone methylation. The structural basis of histone ubiquitination and its interaction with chromatin-modifying complexes has been studied, revealing diverse mechanisms of cross-talk between ubiquitin and other modifications. Beyond lysine ubiquitination, the discovery of linear ubiquitin chains and non-canonical linkages, such as oxyster and phosphoribosyl linkages, has challenged the traditional view of ubiquitin conjugation. These findings highlight the complexity of ubiquitin signaling and its importance in various cellular processes. The article concludes by emphasizing the significance of ubiquitin in cell biology and the potential for therapeutic applications, such as PROTACs and small-molecule inhibitors.The article discusses the evolving understanding of ubiquitin, a small protein that plays a crucial role in various cellular processes beyond protein degradation. Initially discovered in 1975, ubiquitin was found to be involved in protein degradation through the K48-linked polyubiquitin chain. However, recent studies have revealed that ubiquitin also participates in non-degradative functions, such as DNA repair, transcription regulation, and innate immunity. The discovery of non-canonical ubiquitin linkages, such as K63, has expanded the "ubiquitin code," revealing diverse biological roles. The K63-linked polyubiquitin chain is involved in DNA repair and gene silencing, while other linkages, like K6, K11, and K33, have been identified. The structural basis of K63 polyubiquitin chain assembly was elucidated through crystallographic studies, revealing the role of Mms2 in positioning the ubiquitin acceptor towards the active site of Ubc13. Histone ubiquitination has also been shown to play a role in transcription and the DNA damage response. For example, the ubiquitination of H2A-K119 is necessary for gene silencing, and the ubiquitination of H2A-K15 serves as a marker for DNA damage repair. Other histone ubiquitination marks, such as H2B-K120, are involved in transcription activation by promoting histone methylation. The structural basis of histone ubiquitination and its interaction with chromatin-modifying complexes has been studied, revealing diverse mechanisms of cross-talk between ubiquitin and other modifications. Beyond lysine ubiquitination, the discovery of linear ubiquitin chains and non-canonical linkages, such as oxyster and phosphoribosyl linkages, has challenged the traditional view of ubiquitin conjugation. These findings highlight the complexity of ubiquitin signaling and its importance in various cellular processes. The article concludes by emphasizing the significance of ubiquitin in cell biology and the potential for therapeutic applications, such as PROTACs and small-molecule inhibitors.