Abstract: The approval of proteasome inhibitors-bortezomib and carfilzomib for the treatment of multiple myeloma by FDA validates the potential of proteasome as a promising anti-cancer drug target. Due to the better selectivity and fewer side effects of epoxyketone peptidyl proteasome inhibitors, they have attracted increasing attentions. The structure and function of proteasome and the mechanism of interactions between proteasome and epoxyketone analogues together with the research progress of this series of compounds are going to be reviewed in this manuscript.