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Tumor cells that are insensitive to anticancer drugs frequently have a multidrug-resistant (MDR) phenotype. Proteins that can be involved in this phenomenon are transport-associated proteins such as P-glycoprotein, multidrug-resistance protein 1, breast cancer resistance protein, and lung resistance-related protein (LRP). LRP was identified as the major vault protein (MVP), the main component of multimeric vault particles. With the recent identification of the two minor vault proteins as telomerase-associated protein (TEP1) and vault-poly (ADP-ribose) polymerase (VPARP), and with high-resolution three-dimensional imaging, the composition of vaults is almost unraveled. Although the first direct evidence for a causal relationship between LRP/MVP expression and drug resistance has been obtained, many functional aspects of vaults in normal physiology and in MDR still need to be clarified. The current clinical data on LRP/MVP detection indicate that LRP/MVP expression can be of high clinical value to predict the response to chemotherapy of several tumor types.