Many antineoplastic agents fail because of intrinsic or acquired resistance developed by the cancer cells; drug resistance is therefore a major obstacle to successful chemotherapy of human cancers, including ovarian cancer. Understanding the mechanisms by which drug resistance arises and identification of the molecular factors affecting new drug target development is of paramount importance. In a study to compare the global RNA expression profiles of primary and recurrent ovarian tumors from the same patient by means of oligonucleotide microarray analysis, we have identified XIST (inactive X [Xi] chromosome-specific transcripts) as the most differentially expressed gene that was downregulated in the recurrent tumor. The XIST gene resides within the X inactivation center and is unique in being expressed exclusively from the inactive X chromosome. XIST is both necessary and sufficient for X inactivation. Preliminary studies of the cell line derived from the recurrent tumor showed that the line is resistant to the antineoplastic agent taxol, one of the anticancer drugs included in the treatment of the patients under study. The recurrent cell line has at least one copy of XIST in the genome, although the gene is not expressed. Further characterization of XIST expression in a panel of ten ovarian cell lines and six breast cancer cell lines showed that the expression levels of XIST correlate significantly with taxol sensitivity. These data indicate a possible correlation between X inactivation and taxol resistance in ovarian cancer. We have launched a detailed mechanistic study to characterize the underlying mechanism.