Programmable genome editing enables heritable genetic modifications for livestock production, disease resistance, and animal welfare. However, its translational maturity across species and traits has not been systematically benchmarked against breeding-program standards. To address this gap, we conducted a systematic review following PRISMA 2020 guidelines. The Web of Science Core Collection (SCI-Expanded) was searched for peer-reviewed articles published between 2010 and 2026 using terms spanning ZFN, TALEN, CRISPR–Cas systems, base editors, prime editors, livestock, animal breeding, and biosafety. A total of 1,326 records were identified; 526 underwent full-text assessment, and 133 met eligibility criteria for qualitative synthesis. A quantitative subset of 28 primary experimental studies reporting editing efficiency, mosaicism, or multigenerational transmission was subjected to structured cross-study comparison. CRISPR–Cas9 was used in 24 of the 28 quantitative studies; notably, no primary livestock study reported founder-level quantitative data for base or prime editing. Across embryo-stage knockout studies, the median on-target efficiency was 84% (range: 45–100%). While SCNT-derived founders were uniformly non-mosaic by clonal design, mosaicism in zygote-edited animals ranged from 20 to 100%. Off-target analysis was reported in 43% of studies, but only 11% employed whole-genome sequencing (WGS). Multigenerational validation beyond founders was documented in 25% of studies, with three reaching the F2 generation or equivalent. Species-level maturity was highest for porcine CD163 editing, which demonstrated multigenerational, production-relevant validation for PRRSV resistance. No primary study identified in this review reported replicated parent–offspring trio-based WGS in directly zygote-edited livestock under contemporary methodological standards. For somatic cell nuclear transfer (SCNT)-derived founders, variant analysis was typically performed relative to the unedited donor cell line, and genome-wide assessments in this context have reported low off-target variant burdens relative to donor baselines, although cross-study comparability remains limited by heterogeneity in sequencing depth, variant-calling pipelines, and reporting thresholds. Finally, unintended on-target structural alterations, including plasmid backbone integration, were documented in SCNT-derived cattle. A robust proof-of-concept has been achieved for monogenic trait editing in pigs and cattle, yet the evidence base for breeding-scale deployment remains limited. Critical gaps include the absence of trio-based off-target baselines, a lack of cross-platform structural variant comparisons, and the unvalidated integration of computational tools within livestock editing pipelines. Responsible translation requires molecular validation depth proportional to dissemination intent as well as multi-generational, multi-environment performance data prior to commercialization. Graphical Abstract The alternative text for this image may have been generated using AI.