PURPOSE OF REVIEW: Living donor liver transplantation (LDLT) increasingly depends on biologically related donors, particularly in Asia and the Middle East, where deceased donation remains limited. This review evaluates genetic risks in living donors and proposes a system-based approach to donor selection. RECENT FINDINGS: Heterozygous carriers exhibit variable functional capacity determined by enzyme thresholds and epigenetic mechanisms such as X-chromosome lyonization. In ornithine transcarbamylase deficiency (OTCD), maternal donors may have insufficient enzymatic activity, resulting in donor risk and incomplete metabolic correction. Conversely, certain autosomal recessive disorders permit safe use of heterozygous donors within defined functional limits. In regions with high consanguinity, especially in parts of the Middle East, hereditary liver diseases are more prevalent, increasing the likelihood that potential donors share pathogenic variants. Additionally, reports of acute liver failure following gene therapy in Duchenne muscular dystrophy (DMD) highlight systemic vulnerability in genetically affected individuals. SUMMARY: Donor evaluation must extend beyond anatomical suitability to include disease-specific genetic risk assessment. A system-based, globally informed framework integrating genomics, functional assessment, and multidisciplinary oversight is essential to ensure donor safety and optimize outcomes.