This study used gene expression profiling of multiple myeloma samples to identify genes involved in drug resistance. Expression of NEK2, a chromosomal instability gene that encodes a protein kinase, was correlated with drug resistance (through the activation of efflux pumps), rapid relapse and poor outcome in multiple myeloma and other cancers. RNA-mediated knockdown of NEK2 overcame drug resistance and induced apoptosis in a xenograft mouse model of multiple myeloma, suggesting that NEK2 could act as a marker of drug resistance and poor prognosis as well as a new target for therapy.