Adeno-associated viral vectors have proven to be a safe and effective gene therapy delivery system. Over the past decade, the approval of AAV gene therapies made a revolution in treatment of severe hereditary diseases, including spinal muscular atrophy, AADC deficiency, and others. Recombinant AAV-based therapeutics are currently intended for single administration. Safety concerns arise from immune responses to AAV and the resulting transgene, which can render subsequent injections ineffective. It remains unclear whether patients who have received an AAV-based gene therapy will need re-administration in the future. Furthermore, since many people have neutralizing antibodies or memory T cells against AAV from natural infections, it is crucial to overcome pre-existing immunity. This review considers existing modern approaches aimed to overcome both pre-existing natural immunity and immunity obtained after the administration of a gene therapy drug, which include various modifications of the viral drug (capsid modification, codon optimization), the use of empty capsid traps, and pharmacological support (immunosuppressive corticosteroids, inhibitors of various branches of the immune response, nanoparticles, IgG-degrading enzymes). The goal of this review is to illustrate the importance of this challenge and to highlight potential strategies for overcoming immunity to AAV-based gene therapies, contributing to the development of a successful therapeutic gene delivery platform.