Duchenne Muscular dystrophy (DMD) is one of the most severe forms of hereditary diseases in muscles. The identification and characterization of dystrophin, the gene responsible for the disease has lead to the development of potential gene therapy treatments for this disorder. The complex structure and size of the dystrophin gene represent a challenge for some gene therapy approaches such as gene replacement mediated by viral vectors. Others, including oligonucleotide-mediated gene therapies have allowed forms of manipulation in the dystrophin gene not possible with other disorders. The use of oligonucleotides to modulate gene expression has shown to be a feasible alternative treatment to DMD. Antisense-mediated technologies have made outstanding progress in the last decade and two phase I clinical trials for exon skipping in DMD are already in progress. Gene correction mediated by oligonucleotides faces much greater obstacles, but the outcome of the approach, permanent correction of the gene defect, represents an ideal treatment to the disease. Gene therapy mediated by antisense oligonucleotides or oligonucleotide mediated gene editing have the potential to have a primary role in gene therapy applications to muscles, but they are still far from representing an effective cure. Factors like safety and sustained beneficial effects in patients will have to be considered in detail before this technology can become applicable to the treatment of muscles disorders. Ultimately the need for production of oligonucleotides in large scale and the cost of treatment for each individual patient will play a big role in the feasibility of these approaches in DMD.