The article reviews the progress and challenges in liver-directed gene therapy for inherited metabolic diseases. It highlights the use of adeno-associated virus (AAV) vectors and other gene therapy vectors, including lentiviral and lipid nanoparticle (LNP)-encapsulated mRNA, for correcting genetic defects in the liver. The review covers various diseases such as urea cycle disorders, organic acidemias, Crigler-Najjar syndrome, Wilson disease, glycogen storage disease Type Ia, phenylketonuria, and maple syrup urine disease. Key strategies include gene replacement, gene augmentation, and gene editing using CRISPR-Cas9. The article discusses the limitations and open questions, such as immunogenicity, inflammatory response, genotoxicity, and gene therapy administration in fibrotic livers. It emphasizes the importance of long-term follow-up to monitor safety and efficacy, and concludes that liver-directed gene therapy offers a promising avenue for treating inherited metabolic diseases.The article reviews the progress and challenges in liver-directed gene therapy for inherited metabolic diseases. It highlights the use of adeno-associated virus (AAV) vectors and other gene therapy vectors, including lentiviral and lipid nanoparticle (LNP)-encapsulated mRNA, for correcting genetic defects in the liver. The review covers various diseases such as urea cycle disorders, organic acidemias, Crigler-Najjar syndrome, Wilson disease, glycogen storage disease Type Ia, phenylketonuria, and maple syrup urine disease. Key strategies include gene replacement, gene augmentation, and gene editing using CRISPR-Cas9. The article discusses the limitations and open questions, such as immunogenicity, inflammatory response, genotoxicity, and gene therapy administration in fibrotic livers. It emphasizes the importance of long-term follow-up to monitor safety and efficacy, and concludes that liver-directed gene therapy offers a promising avenue for treating inherited metabolic diseases.