Our group harnesses next-generation genome editing tools for chemical genetic approaches. In one major direction, we have advanced CRISPR mutational scanning approaches to interrogate protein structure-function and small molecule mechanism of action. These approaches enable the broad and systematic identification of functional mutations across endogenous proteins of interest. We study key mutations in deeper mechanistic studies using any method at our disposal, enabling us to deconvolute small molecule mechanism, uncover sites of protein functionality and allosteric regulation, and identify new cancer dependencies. We have expanded these approaches to investigate multi-subunit complexes and pathways, employ new forms of precision genome-editing and single-cell technologies, and explore the mechanisms of diverse small molecule modalities. To enable these and other efforts, we pursue the chemical synthesis of small molecules and their functional derivatives. Ongoing projects are focused on exploring chromatin complexes, transcription factors, signaling molecules, and E3 ubiquitin ligases. Our long-term goal is to leverage large-scale chemical-genomic maps with mechanistic insight for the development of therapeutic approaches.