Effective, non-toxic therapies for many diseases, including malignancies, metabolic syndromes and age-dependent neurodegeneration remain elusive, though not for lack of effort from scientists all over the world. To effectively treat a disease we need to understand what goes wrong at the cellular level, identify the molecular players involved and co-opt cellular pathways through targeted therapeutics. It is becoming increasingly clear that a large family of enzymes, the deubiquitinases or DUBs, play fundamental roles in health and disease. DUBs are cysteineor Zn2+-dependent metallo-proteases that fulfill their molecular duties by cleaving covalent bonds between the protein modifier ubiquitin and substrate proteins. Post-translational modification of proteins by ubiquitin regulates numerous cellular processes, including cell division, gene transcription, protein degradation, intra-cellular and inter-cellular communication. Ubiquitin-dependent pathways are dysregulated in many diseases. Conjugation of ubiquitin to a substrate protein usually alters its interaction partners. By changing its interaction properties, ubiquitination can therefore change a protein’s subcellular localization (e.g. send it to the nucleus, or internalize a trans-membrane receptor), target it for degradation by the proteasome or through autophagy, or change its activity (activation or inhibition). By cleaving off ubiquitin from substrates, DUBs regulate their fate and in turn control various cellular pathways.