Since the discovery of RNA splicing in 1977, significant strides have been made in understanding its role in human development and disease. Splice modulation, particularly exon skipping and exon inclusion, have emerged as a promising therapeutic strategy to correct genetic disorders caused by recessive loss-of-function mutations. Exon skipping and exon inclusion involve the use of antisense oligonucleotides (AOs) to mask specific splice sites or regulatory elements on pre-mRNA, enabling the exclusion or inclusion of exons and restoration of the correct reading frame. This process has gained significant attention due to its application in treating Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and other genetic disorders. The FDA has approved several AO therapies using exon skipping, including eteplirsen, viltolarsen, casimersen, and golodirsen for DMD and nusinersen for SMA. This chapter explores the early history, evolution, and clinical applications of AO-based splice modulation therapies, focusing on exon skipping, one of the most developed strategies.