Gene knockout is the primary method for studying gene function and generating disease models. Because mutations may be compensated for by paralogous genes and many diseases are multigenic, simultaneous knockout is a long sought-after tool. Whereas standard CRISPR methods rely on the introduction and repair of double-stranded breaks (which can have deleterious effects on the cell), the recently developed CRISPR-stop method makes use of base editors to change a single nucleic acid and create a premature stop codon. In this issue, Zhang et al. apply CRISPR-stop to generate single and triple gene knockouts in F0 mice with extremely high efficiency. As targets, the authors selected genes important for the formation or function of hair cells in the inner ear (Atoh1, prestin, vGlut3 and otoferlin). Using Atoh1 for benchmarking, they found that when injecting two in vitro-validated sgRNAs per target, homozygous zygotic mutants could be created with an efficiency between 63.6% and 100%. They then went on to generate three different deafness models by targeting prestin, vGlut3 and otoferlin, and confirmed the individual loss of these genes by DNA sequencing, immunostaining and functional analyses. Finally, the authors simultaneously targeted all three genes (with doubled dosages of sgRNAs per target relative to single gene knockout) and obtained homozygous triple mutant mice with nearly 100% efficiency and without off-target effects. Thus, this technique will make mouse geneticists’ lives much easier by replacing laborious mouse breeding when generating animals with multiple gene knockouts.