The ubiquitin-proteasome-system is an essential cellular pathway that regulates stability and function of proteins. In cancer cells ubiquitination is frequently deregulated by mutation or aberrant expression of ubiquitin ligases and deubiquitinating enzymes. Moreover, recently we and others found that drugs like thalidomide analogs hijack ubiquitin ligases to rapidly degrade cancer-related proteins including those that were previously considered undruggable such as transcription factors. The focus of our research is to determine the impact of deregulated protein ubiquitination and protein stability in hematologic malignancies. We apply comprehensive proteomic and genetic analyses in primary patient samples combined with CRISPR/Cas9 functional genetics to uncover disease driving and resistance mediating alterations in the ubiquitin-proteasome system. In addition, we study new compounds like proteolysis-targeting chimeras (PROTACs) that direct ubiquitin ligases to proteins as targeted treatments for cancer. The ultimate goal is to translate our findings into the clinic for personalized treatments.