Developments in CRISPR/Cas9-based technologies provide a new paradigm in functional screening of the genome. Conventional screening methods have focused on high-throughput perturbations of the protein-coding genome with technologies such as RNAi. However, equivalent methods for perturbing the non-coding genome have not existed until recently. CRISPR-based screening of genomic DNA has enabled the study of both genes and non-coding gene regulatory elements. Here we review recent progress in assigning function to the non-coding genome using CRISPR-based genomic and epigenomic screens, and discuss the prospects of these technologies to transforming our understanding of genome structure and regulation.