Drug combinations are commonly used to counter drug resistance in cancer therapy. To identify synergistic drug target combinations, Han et al. have developed a scalable CRISPR-based double-knockout system that enables parallel pairwise gene knockout. Application of this system in a chronic myeloid leukaemia (CML) cell line generated the largest mammalian genetic interaction map to date, which comprises 490,000 single guide RNAs against 21,321 drug target combinations. The predicted target pairs translated to potent synergistic drug combinations in CML cells, including imatinib-resistant cells.