Protein post-translational modification by ubiquitin (Ub) is a versatile signaling system that regulates various aspects of normal cell biology and pathogenesis, governed by a complex enzymatic network. With over 700 enzymes involved, studying the ubiquitination system and developing related therapeutics are vital areas of current research. In this seminar, I will discuss our team's efforts to decode and manipulate the Ub system. Gaining a detailed understanding of this system is both challenging and essential, and chemistry provides valuable tools for uncovering new insights into ubiquitination dynamics. Through the development of cutting-edge platform technologies, including assays, reagents, and probes, we aim to exert control over the Ub system. Our work has laid the groundwork for accelerating the creation of small molecule inhibitors and chemical probes, which hold great promise for advancing our understanding and manipulation of ubiquitin dynamics.