The family of deubiquitinating enzymes (DUBs) comprises more than 100 proteases that catalyze the removal of ubiquitin from substrate proteins, regulating the stability and/or activity of a large fraction of the proteome. DUBs perform key roles in virtually all physiological and pathophysiological processes. Notably, inactivation of specific DUBs promotes proteasomal degradation of substrate proteins, some of which contribute to cancer, infection, neurodegeneration, and other human disease. Despite intense interest in their function and potential as therapeutic targets, there are few selective small molecule probes for DUBs and no approved DUB-targeting drugs. Our long-term goal is to develop a robust, well-validated small molecule inhibitor library for DUBs and then use these to interrogate DUB function in normal physiology and human disease. I will present our progress in developing novel DUB targeting compounds for treatment of hematological malignancies.