POH1/Rpn11/PSMD14 is a highly conserved protein in eukaryotes from unicellular organisms to human and has a crucial role in cellular homoeostasis. It is a subunit of the regulatory particle of the proteasome, where it acts as an intrinsic deubiquitinase removing polyubiquitin chains from substrate proteins. This function is not only coupled to the translocation of substrates into the core of the proteasome and their subsequent degradation but also, in some instances, to the stabilisation of ubiquitinated proteins through their deubiquitination. POH1 was initially discovered as a functional homologue of the fission yeast gene pad1 + , which confers drug resistance when overexpressed. In translational studies, expression of POH1 has been found to be increased in several tumour types relative to normal adjacent tissue and to correlate with tumour progression, higher tumour grade, decreased sensitivity to cytotoxic drugs and poor prognosis. Proteasome inhibitors targeting the core particle of the proteasome are highly active in the treatment of myeloma, and recently developed POH1 inhibitors, such as capzimin and thiolutin, have shown promising anticancer activity in cell lines of solid tumours and leukaemia. Here we give an overview of POH1 function in the cell, of its potential role in oncogenesis and of recent progress in developing POH1-targeting drugs.