Bioinformatic algorithms have predicted many microRNA (miRNA) targets known as miRNA response elements (MREs), but studying their relevance in vivo remains challenging. Bassett et al. used genome editing to disrupt endogenous MREs, which allowed them to characterize specific miRNA–target interactions in zebrafish embryos and fruitflies. They also developed a new method to custom-edit MREs in human cell cultures using CRISPR-mediated homology-directed repair with short oligonucleotides.