Nearly every cancer patient is treated with chemotherapy yet our understanding of factors that dictate response and resistance to such agents remains limited. We report the generation of a quantitative chemical-genetic interaction map in human mammary epithelial cells that charts the impact of knockdown of 625 cancer and DNA repair related genes on sensitivity to 29 drugs, covering all classes of cancer chemotherapeutics. This quantitative map is predictive of interactions maintained in cancer cell lines and can be used to identify new cancer-associated DNA repair factors, predict cancer cell line responses to therapy and prioritize drug combinations. We identify that GPBP1 loss in breast and ovarian cancer confers resistance to cisplatin and PARP inhibitors through the regulation of genes involved in homologous recombination. This map may help navigate patient genomic data and optimize chemotherapeutic regimens by delineating factors involved in the response to specific types of DNA damage.