The efficacy of cisplatin-based chemotherapy is often reduced by the emergence of cancer cells that become resistant to the treatment used. While biochemical and pharmacological mechanisms have been proposed to explain cisplatin resistance, the genes involved in this process have until recently become understood. To further understand the mechanisms underlying chemoresistance, we earlier used genome-wide DNA microarrays and quantitative RT-PCR to identify the genes that were upregulated in cisplatin-resistant HeLa cells. By using this approach, we identified nine genes, referred to as cisplatin resistance (CPR) genes, which were consistently upregulated in resistant cells. CPR genes were found to encode various extracellular (ADM), cytoplasmic (EHD1, MARK2, MVD, NAPA, and PTPN21), and nuclear proteins (CABIN1, CITED2, and HIST1H1A). The involvement of CPR proteins in chemoresistance was demonstrated by showing that reducing their expression by using short-hairpin RNA (shRNA) could sensitize various cell lines to cisplatin, but not to mitosis-disrupting agents. As such, knockdown of CPR genes partially or entirely reversed acquired chemoresistance. Conversely, ectopic expression of a single CPR gene was sufficient to enhance cisplatin resistance in the treated cells. The cisplatin-sensitization effects of shRNA-mediated CPR gene knockdowns (e.g., NAPA and CITED2) was shown to require the tumor suppressor p53. Importantly, combined cisplatin/shRNA treatments suppressed tumor growth in vivo in xenograph experiments performed in mice, thereby indicating that the newly identified CPR genes may represent potential candidates for novel target therapies.