Ubiquitylation is an essential cellular process, and yet many cancer cells appear to be more reliant upon it than normal cells as they are surprisingly sensitive to proteasome inhibitors (PI) and proteasome inhibitor drugs are well tolerated in vivo. Several reviews have suggested that specific protein targets account for PI induced cell death, but fail to adequately explain why cancer cells are more sensitive than normal cells to PIs. We review the evidence for these models, focusing primarily on inducers of cell death including p53 and the pro-apoptotic Bcl-2 Homology proteins (BH3 proteins) and propose an additional hypothesis; that a tumour cells abnormal physiology makes it particularly reliant upon the proteasome. This hypothesis is well supported in the case of Multiple Myelomas, that may produce large amounts of antibodies and are therefore under considerable ER strain and in turn particularly reliant upon the proteasome to clear the large numbers of misfolded proteins. We propose that other cell types, tumor or non tumour, that are already under ER stress, or its equivalent, maybe particularly susceptible to proteasome inhibitors.