Oligonucleotide (ON)-based therapies, particularly exon skipping and inclusion strategies, have revolutionized the treatment landscape for genetic and rare diseases, heralding a new era in personalized medicine. This chapter traces the evolution of ON therapeutics, from pioneering efforts in the 1970s to their resurgence as cutting-edge treatments in the twenty-first century. Highlighting seminal developments, such as the approval of splice-switching ONs like eteplirsen for Duchenne Muscular Dystrophy and nusinersen for Spinal Muscular Atrophy, it underscores the critical role of these therapies in advancing patient-specific treatments. Despite their promising potential, exon skipping and inclusion therapies encounter challenges related to delivery, stability, and regulatory hurdles. Commemorating the silver jubilee of the first ON therapy approval, this narrative not only celebrates the achievements but also critically examines the ongoing challenges and the imperative for sustained innovation and collaboration. The chapter aims to illuminate the path forward, emphasizing the need to harness the full promise of exon skipping and inclusion therapies in personalized genetic medicine.