Antisense oligonucleotides (ASOs) have shown significant success in clinical applications for treating inherited metabolic diseases (IEMs). Eight ASO drugs have been approved by the FDA since 1998, with the first ASO, fomivirsen, approved in 1998. Splice-modulating ASOs are particularly effective for IEMs, as they can correct aberrant splicing caused by mutations, restoring normal protein function. The FDA approved the first "N-of-1" study of milasen for Batten disease in 2018, demonstrating the feasibility of ASOs for IEM treatment. Despite the rarity of individual IEMs, splice-switching ASOs offer personalized molecular therapies. ASOs are designed to target specific pathogenic mutations, and their effectiveness is enhanced by chemical modifications such as phosphorothioate (PS), 2'-O-methoxyethyl (2'-MOE), and locked nucleic acid (LNA). These modifications improve the stability, specificity, and efficacy of ASOs. ASOs have been developed for various IEMs, including lysosomal storage diseases, organic acidemias, and congenital disorders of glycosylation. Current research focuses on improving ASO development for IEMs, with a focus on optimizing their pharmacokinetics and pharmacodynamics. ASOs have been approved for several IEMs, including Batten disease, Pompe disease, Fabry disease, and Niemann-Pick type C disease. These ASOs work by correcting aberrant splicing, restoring normal protein function, and improving patient outcomes. The development of ASOs for IEMs continues to advance, with ongoing research aimed at improving their efficacy and safety.Antisense oligonucleotides (ASOs) have shown significant success in clinical applications for treating inherited metabolic diseases (IEMs). Eight ASO drugs have been approved by the FDA since 1998, with the first ASO, fomivirsen, approved in 1998. Splice-modulating ASOs are particularly effective for IEMs, as they can correct aberrant splicing caused by mutations, restoring normal protein function. The FDA approved the first "N-of-1" study of milasen for Batten disease in 2018, demonstrating the feasibility of ASOs for IEM treatment. Despite the rarity of individual IEMs, splice-switching ASOs offer personalized molecular therapies. ASOs are designed to target specific pathogenic mutations, and their effectiveness is enhanced by chemical modifications such as phosphorothioate (PS), 2'-O-methoxyethyl (2'-MOE), and locked nucleic acid (LNA). These modifications improve the stability, specificity, and efficacy of ASOs. ASOs have been developed for various IEMs, including lysosomal storage diseases, organic acidemias, and congenital disorders of glycosylation. Current research focuses on improving ASO development for IEMs, with a focus on optimizing their pharmacokinetics and pharmacodynamics. ASOs have been approved for several IEMs, including Batten disease, Pompe disease, Fabry disease, and Niemann-Pick type C disease. These ASOs work by correcting aberrant splicing, restoring normal protein function, and improving patient outcomes. The development of ASOs for IEMs continues to advance, with ongoing research aimed at improving their efficacy and safety.