CRISPR-based genetic screens have revolutionized the search for new gene functions and biological mechanisms. However, widely used pooled screens are limited to simple read-outs of cell proliferation or the production of a selectable marker protein. Arrayed screens allow for more complex molecular read-outs such as transcriptome profiling, but they provide much lower throughput. Here we demonstrate CRISPR genome editing together with single-cell RNA sequencing as a new screening paradigm that combines key advantages of pooled and arrayed screens. This approach allowed us to link guide-RNA expression to the associated transcriptome responses in thousands of single cells using a straightforward and broadly applicable screening workflow.