The ubiquitin system is essential for maintaining cellular homeostasis and regulating a wide range of cellular functions. Dysfunction of this system is linked to various diseases, particularly neurodegenerative disorders. Despite its importance, the mechanisms underlying its physiological and pathophysiological roles remain poorly understood due to its complexity. The system involves numerous substrate proteins, ubiquitin ligases (E3s), and deubiquitinating enzymes (DUBs), with multiple types of ubiquitination, such as monoubiquitination, multiubiquitination, and polyubiquitination, playing distinct roles. The special issue "Ubiquitin System" aims to enhance understanding of the biochemical, structural, and pathophysiological aspects of the ubiquitin system. Of the 25 submissions, 18 papers were selected for publication. Several articles highlight the role of ubiquitination in regulating intracellular signaling pathways. For example, ubiquitination influences TGF-β signaling, where USP15 has dual functions in both tumor suppression and promotion. Similarly, ubiquitination regulates MAPK signaling, with MEKK1 undergoing self-ubiquitination to control phosphorylation events. RNF7 is a novel regulator of NF-κB signaling, reducing ubiquitination of MALT1 and NEMO without affecting their protein levels. Ubiquitination also contributes to the desensitization and downregulation of G protein-coupled receptors (GPCRs), with studies in Dictyostelium providing insights into its role in GPCR signaling. The ubiquitin system is crucial for cellular homeostasis and responding to stress. Research shows that deubiquitination of amino acid transporters may regulate amino acid transport in response to energy status. Ubiquitination of phospholipan (PLN) is involved in cardiac contractility, with pVHL playing a role in heart failure under oxidative stress. The ubiquitin system also regulates E2F1 transcription factor during cell cycle progression and DNA damage response. Additionally, the ubiquitin system is involved in autoimmune and inflammatory diseases, such as arthritis and psoriasis, with studies on proteasome inhibitors showing potential therapeutic applications. The functions and regulatory mechanisms of ubiquitination are becoming increasingly complex, with new substrates, regulators, and ubiquitin chain patterns being identified. The special issue provides new insights into the biochemical, pathological, and therapeutic aspects of the ubiquitin system. The author thanks the contributors and reviewers for their work. This work was supported by the Japan Society for the Promotion of Science. The author declares no conflict of interest.The ubiquitin system is essential for maintaining cellular homeostasis and regulating a wide range of cellular functions. Dysfunction of this system is linked to various diseases, particularly neurodegenerative disorders. Despite its importance, the mechanisms underlying its physiological and pathophysiological roles remain poorly understood due to its complexity. The system involves numerous substrate proteins, ubiquitin ligases (E3s), and deubiquitinating enzymes (DUBs), with multiple types of ubiquitination, such as monoubiquitination, multiubiquitination, and polyubiquitination, playing distinct roles. The special issue "Ubiquitin System" aims to enhance understanding of the biochemical, structural, and pathophysiological aspects of the ubiquitin system. Of the 25 submissions, 18 papers were selected for publication. Several articles highlight the role of ubiquitination in regulating intracellular signaling pathways. For example, ubiquitination influences TGF-β signaling, where USP15 has dual functions in both tumor suppression and promotion. Similarly, ubiquitination regulates MAPK signaling, with MEKK1 undergoing self-ubiquitination to control phosphorylation events. RNF7 is a novel regulator of NF-κB signaling, reducing ubiquitination of MALT1 and NEMO without affecting their protein levels. Ubiquitination also contributes to the desensitization and downregulation of G protein-coupled receptors (GPCRs), with studies in Dictyostelium providing insights into its role in GPCR signaling. The ubiquitin system is crucial for cellular homeostasis and responding to stress. Research shows that deubiquitination of amino acid transporters may regulate amino acid transport in response to energy status. Ubiquitination of phospholipan (PLN) is involved in cardiac contractility, with pVHL playing a role in heart failure under oxidative stress. The ubiquitin system also regulates E2F1 transcription factor during cell cycle progression and DNA damage response. Additionally, the ubiquitin system is involved in autoimmune and inflammatory diseases, such as arthritis and psoriasis, with studies on proteasome inhibitors showing potential therapeutic applications. The functions and regulatory mechanisms of ubiquitination are becoming increasingly complex, with new substrates, regulators, and ubiquitin chain patterns being identified. The special issue provides new insights into the biochemical, pathological, and therapeutic aspects of the ubiquitin system. The author thanks the contributors and reviewers for their work. This work was supported by the Japan Society for the Promotion of Science. The author declares no conflict of interest.