H11-CAG-hCas mice carry a targeted insertion of the Cas endonuclease expression cassette, driven by the ubiquitous CAG promoter. This configuration ensures systemic expression of Cas protein across tissues. Notably, constitutive Cas expression in these mice does not elicit detectable toxicity, morphological abnormalities, tumorigenesis, or activation of DNA damage or apoptotic pathways. In the presence of sequence-specific single-guide RNAs (sgRNAs), this model enables efficient and simultaneous editing of single or multiple genes. H11-CAG-hCas mice are viable, fertile, and well-suited for a wide range of genome engineering applications.