Liver-directed gene therapy is increasingly used to treat inherited metabolic liver diseases, with two gene therapy products already approved for liver-based monogenic disorders. This review discusses various gene therapy vectors and strategies for liver targeting, including gene editing, and highlights current developments in treating conditions such as urea cycle defects, organic acidemias, Crigler–Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria, and maple syrup urine disease. The review also addresses challenges such as immunogenicity, inflammatory response, genotoxicity, and gene therapy administration in fibrotic livers. The growing number of gene therapy-treated patients provides insights into its benefits and limitations, aiding in the design of safer and more effective treatments. Liver-targeting gene therapy offers a promising avenue for innovative therapies, with the potential to address unmet needs in inherited metabolic diseases. Current approaches include viral and nonviral vectors, with AAV vectors showing the greatest clinical success for in vivo liver gene therapy. However, challenges such as immunogenicity, inflammatory response, and genotoxicity remain. Non-viral strategies using lipid nanoparticles (LNPs) for mRNA delivery have shown promise in targeting the liver. Gene editing techniques such as CRISPR-Cas9, base editing, and prime editing have demonstrated efficacy in preclinical models. Despite these advancements, open issues include the need for improved vectors, long-term safety, and the potential for insertional mutagenesis. The review also discusses the application of gene therapy in specific diseases, such as urea cycle disorders, Crigler–Najjar syndrome, organic acidemias, Wilson disease, glycogen storage disease Type Ia, and maple syrup urine disease. The review concludes that liver-targeting gene therapy is revolutionizing the treatment of inherited metabolic diseases, with ongoing research aimed at improving safety and efficacy.Liver-directed gene therapy is increasingly used to treat inherited metabolic liver diseases, with two gene therapy products already approved for liver-based monogenic disorders. This review discusses various gene therapy vectors and strategies for liver targeting, including gene editing, and highlights current developments in treating conditions such as urea cycle defects, organic acidemias, Crigler–Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria, and maple syrup urine disease. The review also addresses challenges such as immunogenicity, inflammatory response, genotoxicity, and gene therapy administration in fibrotic livers. The growing number of gene therapy-treated patients provides insights into its benefits and limitations, aiding in the design of safer and more effective treatments. Liver-targeting gene therapy offers a promising avenue for innovative therapies, with the potential to address unmet needs in inherited metabolic diseases. Current approaches include viral and nonviral vectors, with AAV vectors showing the greatest clinical success for in vivo liver gene therapy. However, challenges such as immunogenicity, inflammatory response, and genotoxicity remain. Non-viral strategies using lipid nanoparticles (LNPs) for mRNA delivery have shown promise in targeting the liver. Gene editing techniques such as CRISPR-Cas9, base editing, and prime editing have demonstrated efficacy in preclinical models. Despite these advancements, open issues include the need for improved vectors, long-term safety, and the potential for insertional mutagenesis. The review also discusses the application of gene therapy in specific diseases, such as urea cycle disorders, Crigler–Najjar syndrome, organic acidemias, Wilson disease, glycogen storage disease Type Ia, and maple syrup urine disease. The review concludes that liver-targeting gene therapy is revolutionizing the treatment of inherited metabolic diseases, with ongoing research aimed at improving safety and efficacy.