Traditional cell-based phenotypic assays can be powerful, but often suffer from lack of throughput and require the development of bespoke assays for every gene/phenotype one wishes to assess. A compelling alternative approach to address these drawbacks is to use cellular signatures, such as transcription, to capture meaningful phenotypes in a pathway-agnostic fashion. Additionally, the use of droplet-based single-cell RNA sequencing to assess these signatures enables unprecedented scale and resolution in cellular screens, and enables the simultaneous assessment of large perturbation libraries across numerous cellular contexts. We are developing methods to enable massively multiplexed single-cell transcriptional profiling for the characterization of cancer variants, for CRISPR & small molecule screening, and for the characterization of common and rare genetic variants in human health and disease.