Antisense oligonucleotides (ASOs) are among the most explored therapeutic approaches for DM1. Different ASO chemistries, including phosphorothioate (PS), 2′O-methyl, 2-methoxyethyl (MOE), phosphorodiamidate morpholino oligomer (PMO) and locked nucleic acid (LNA) modifications, have been developed to improve stability, affinity and cellular uptake. Depending on their design, ASOs can either induce RNA degradation or modulate RNA processing. While several approaches have shown promising results, strategies based on RNA degradation may also affect normal DMPK expression. Therefore, more specific approaches that selectively remove the toxic CUG-expanded region while preserving the transcript are still needed.