The authors demonstrate the feasibility of creating knockout rats using engineered zinc-finger nucleases (ZFNs). By injecting ZFN-encoding DNA or mRNA into one-cell rat embryos, they achieve a high frequency of animals with 25–100% disruption at target loci, including an integrated reporter gene and two endogenous rat genes, *Immunoglobulin M (IgM)* and *Rab38*. The mutations are faithfully and efficiently transmitted through the germline, showing high fidelity at predicted off-target sites. This approach, which can be applied to multiple rat strains within four months, paves the way for a humanized monoclonal antibody platform and additional human disease models.The authors demonstrate the feasibility of creating knockout rats using engineered zinc-finger nucleases (ZFNs). By injecting ZFN-encoding DNA or mRNA into one-cell rat embryos, they achieve a high frequency of animals with 25–100% disruption at target loci, including an integrated reporter gene and two endogenous rat genes, *Immunoglobulin M (IgM)* and *Rab38*. The mutations are faithfully and efficiently transmitted through the germline, showing high fidelity at predicted off-target sites. This approach, which can be applied to multiple rat strains within four months, paves the way for a humanized monoclonal antibody platform and additional human disease models.