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A major difference between animal models and human pathology is the extent of fibrosis observed. Progressive and irreversible fibrosis needs to be targeted before or alongside genetic strategies. Fibrosis limits muscle function through a collagen\u2010rich extracellular matrix (ECM) that forms a stiff barrier impeding penetration of gene therapy vectors, such as adeno\u2010associated viruses (AAVs). It disrupts the satellite cell niche, compromising activation, proliferation, and differentiation. Even with successful gene delivery, regeneration in fibrotic muscle is severely impaired. Recent reports of acute liver toxicity leading to deaths in gene therapy trials using the AAVrh74 vector underscore the risks associated with high systemic AAV doses. If fibrosis can be alleviated, effective transduction might be achieved with lower vector quantities in a single therapeutic dose, reducing the systemic risks. Anti\u2010fibrotic agents are being explored to counteract disease progression. 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