Chemical genetic screens are a powerful tool for exploring how cancer cells’ response to drugs is shaped by their mutations, yet they lack a molecular view of the contribution of individual genes to the response to exposure. Here, we present sci-Plex-Gene-by-Environment (sci-Plex-GxE), a platform for combined single-cell genetic and chemical screening at scale. We highlight the advantages of large-scale, unbiased screening by defining the contribution of each of 522 human kinases to the response of glioblastoma to different drugs designed to abrogate signaling from the receptor tyrosine kinase pathway. In total, we probed 14,121 gene-by-environment combinations across 1,052,205 single-cell transcriptomes. We identify an expression signature characteristic of compensatory adaptive signaling regulated in a MEK/MAPK-dependent manner. Further analyses aimed at preventing adaptation revealed promising combination therapies, including dual MEK and CDC7/CDK9 or nuclear factor κB (NF-κB) inhibitors, as potent means of preventing transcriptional adaptation of glioblastoma to targeted therapy. Display omitted •A platform for combined single-cell genetic and chemical screens at scale•Inferred transcriptional EC50 quantifies the effect of perturbation on drug response•Chemical transcriptomics defines a shared adaptive drug-resistance program•Kinome-wide sci-Plex-GxE prioritizes treatment combinations that block adaptation Molecular maps of response to anti-cancer therapy can uncover genes that promote or resist treatment. McFaline-Figueroa et al. introduce sci-Plex-GxE to probe the vast interaction space between genetic perturbations and drug treatments. Applying it to a kinome-wide screen for regulators of drug-induced transcription identified kinases that induce an adaptive resistance program.