The article reviews the progress and potential of splice-modulating antisense oligonucleotides (ASOs) in treating inherited metabolic diseases (IMDs). ASOs are synthetic single-stranded nucleic acids that can bind to precursor mRNA (pre-mRNA) and/or mRNA, modulating gene expression. Over the past decade, eight ASO drugs have been approved by the US FDA, with a focus on treating inborn errors of metabolism (IEMs). Splice-modulating ASOs have shown promise in correcting aberrant splicing caused by mutations, thereby restoring normal transcript expression and correcting protein deficiencies. The first "N-of-1" study of milasen, an ASO for Batten disease, was approved by the FDA in 2018, highlighting the potential of ASOs in treating rare IEMs. The article discusses the mechanisms of ASO action, chemical modifications, and rational design of modified ASOs. It also provides a comprehensive review of current developments in splice-switching ASOs for treating various IEMs, including lysosomal storage diseases, organic acidemias, and congenital disorders of glycosylation. The authors suggest strategies to improve the development of ASOs targeting IEMs, emphasizing the importance of chemical modifications and rational design to enhance therapeutic efficacy and specificity.The article reviews the progress and potential of splice-modulating antisense oligonucleotides (ASOs) in treating inherited metabolic diseases (IMDs). ASOs are synthetic single-stranded nucleic acids that can bind to precursor mRNA (pre-mRNA) and/or mRNA, modulating gene expression. Over the past decade, eight ASO drugs have been approved by the US FDA, with a focus on treating inborn errors of metabolism (IEMs). Splice-modulating ASOs have shown promise in correcting aberrant splicing caused by mutations, thereby restoring normal transcript expression and correcting protein deficiencies. The first "N-of-1" study of milasen, an ASO for Batten disease, was approved by the FDA in 2018, highlighting the potential of ASOs in treating rare IEMs. The article discusses the mechanisms of ASO action, chemical modifications, and rational design of modified ASOs. It also provides a comprehensive review of current developments in splice-switching ASOs for treating various IEMs, including lysosomal storage diseases, organic acidemias, and congenital disorders of glycosylation. The authors suggest strategies to improve the development of ASOs targeting IEMs, emphasizing the importance of chemical modifications and rational design to enhance therapeutic efficacy and specificity.