Tumor resistance to chemotherapeutic DNA damaging agents, such as cisplatin, is an obstacle in the treatment of many cancers, including lung and ovarian. Resistance is influenced by nucleotide excision repair (NER) catalyzed removal of cisplatin-DNA lesions. NER is the primary pathway used by the cells in the repair of helix-distorting cisplatin lesions; therefore, inhibition of NER may increase the efficacy of cisplatin treatment. More specifically, the recognition and verification of DNA damage by NER is a critical step in the pathway, making it an ideal target for inhibition. Recognition of DNA damage occurs primarily through two proteins, Xeroderma Pigmentosum Group A (XPA) and replication protein A (RPA). XPA has been shown to have a role exclusively in NER, thus making it a highly specific target for inhibition that will lead to a decrease in NER and an increase in sensitivity to cisplatin treatment. RPA is a single-stranded DNA-binding protein that has roles in NER as well as in other metabolic pathways, including DNA replication and recombination. We have developed a high-throughput (HT) assay for XPA/RPA binding to DNA and screened libraries of small molecules to identify compounds capable of interrupting the protein/DNA interaction, an effort that has lead to the identification of small molecule inhibitors of both RPA and XPA. These inhibitors have been validated in secondary in vitro screens and structure—activity relationships were determined for one class of inhibitors. Further development of this class of compounds is anticipated to display cytostatic/cytotoxic activity and sensitize cells to cisplatin therapy.