Genome editing of mouse embryos is a potentially rapid means of generating mouse models of human disease, and previous studies have achieved targeted genomic deletions and replacements using zinc finger nucleases (ZFNs). For this purpose, Wefers et al. have now adopted transcription-activator-like effector nucleases (TALENs), which allow more customizable targeting of genomic sequences than do ZFNs. They injected a site-specific TALEN and an engineered DNA replacement cassette into a one-cell mouse embryo to generate a knock-in mutation in Rab38 to model Hermansky–Pudlak syndrome. Heterozygous mutant progeny from this founder mutant were available within 18 weeks.