Researchers have generated a platform that uses combinatorial genetics en masse (CombiGEM) and the CRISPR–Cas9 system for the rapid assembly of barcoded combinatorial genetic libraries that can be tracked with high-throughput sequencing. The approach can be used to undertake pooled combinatorial genetic perturbations in human cells and to identify the synergistic actions of genes that control complex traits. These findings can then be leveraged to determine novel combinatorial drug therapies. Wong et al. applied CombiGEM–CRISPR to create a library of 23,409 barcoded dual guide-RNA combinations. Gene pairs that inhibit ovarian cancer cell growth when targeted were identified by a high-throughput pooled screen and validated by CRISPR–Cas9-mediated knockout or RNA-interference-mediated knockdown assays. Small-molecule drug pairs directed against the identified gene pairs were shown to synergistically inhibit proliferation of ovarian cancer cells.