Pooled knockout screening with CRISPR-Cas9 has revolutionized drug discovery and has evolved to become the backbone of many drug discovery pipelines. Though powerful in its own right, pooled CRISPR screening is often restricted to measuring a single phenotype such as proliferation or cell survival or simple phenotypic changes, such as measurement of changes in a single gene’s activity through the generation of a reporter cell line. To better understand drug responses and the occurrence of treatment resistance, it is key to understand the genetics behind the heterogeneity of response to a particular drug. CRISPR single cell (CRISPRsc) allows for the identification of many more key regulators within a treated population of cells, the driver response to the drug used and unveils genetic interactions relevant to the treatment in particular subsets of cells. CRISPRsc combines the flexibility of pooled screening with the power of transcriptomics at single-cell resolution. By linking a specific guide RNA to single-cell whole-transcriptome readout, CRISPRsc offers the opportunity to interrogate the phenotype of any given genetic perturbation in unprecedented detail.