PROJECT SUMMARY Numerous large sequencing initiatives have produced catalogs of human genetic diversity. A major obstacle in using these data to better understand health and disease is the vast scale of the human genome: for example, there are ~22,000 protein coding genes, millions of candidate regulatory elements, and tens of millions of common variants. This challenge has motivated the development of increasingly refined functional genomics tools that enable many distinct hypotheses to be tested in parallel. For example, CRISPR screening libraries enable every gene in the genome to be systematically knocked out, activated, or knocked down, providing a means of testing how connect genes to phenotype. Though highly successful, these approaches are in one sense rather wasteful: quantification usually amounts to counting the representation of the sgRNAs mediating the perturbations by sequencing, meaning thousands of cells per gene are often used in practice to ensure statistical power. This simple constraint means that screens are often conducted in only a handful of conditions, limits applications to precious cell types such as patient samples, and makes scaling to larger problems difficult. Here we leverage the explosion of recent innovation that has accompanied the popularization of single-cell RNA sequencing to revisit the task of conducting CRISPR screens. We propose Quantitative Reporter Sequencing (QRS), a highly scalable and highly quantitative approach for connecting CRISPR-mediated genetic perturbations to their effects on an engineered phenotypic reporter in pooled format. Using a simple library prep protocol that requires no special instruments, QRS enables CRISPR screens with single-cell resolution and absolute quantification of phenotype. Each cell therefore serves as an independent replicate measurement, reducing cell input requirements and enabling the measurement of distributions of phenotype for each perturbation rather than average effects. Through applications we demonstrate how this approach can be used to conduct highly sensitive screens for weak effects in precious cell types, to efficiently quantify genetic interactions (i.e. emergent effects of perturbing multiple genes simultaneously), and to guide the search for drivers of incompletely penetrant phenotypes. This platform will extend CRISPR-mediated functional genomics to contexts and cell types that are currently intractable and enable experiments that are “beyond genome-scale.”