The Ubiquitin Proteasome System (UPS) controls the principal functions of almost all the cellular proteins of human cells and failures in this system often contribute directly or indirectly to the pathogenesis of many diseases, including cancer, inflammation, and neurodegeneration. There are ~700 E3 ubiquitin ligases encoded in human genome and the functions of most of these E3s remain unknown. E3 ligases build diverse ubiquitin chain linkages on substrates that can determine the fate of the substrate. Whereas K48-linked ubiquitin chains promote proteasomal degradation of substrates, K63-linked ubiquitin chains are associated with signaling and localization. Identification of the type of ubiquitin linkage as well as the substrate lysines modified with ubiquitin can provide insights into the cellular functions of E3s. Lifesensors can perform these studies very efficiently and in a timely manner for the clients.