Genomes are the basis of human biology and human disease. Understanding the role of each gene on a healthy or diseased phenotype requires an intervention to causally link between genotype and phenotype. Advances in RNA-guided endonucleases have enabled such pooled screens in human cells. I first consider a model to understand drivers of immune evasion in a pooled knockout screen conducted in an in vitro model of metastatic melanoma. Next, I discuss strategies for scaling these screens to encompass a larger set of genes from the human genome. Finally, I explore how next-generation genome editors can move beyond knockout screens to identify the biological role of any sequence at any location in the human genome.