Gene therapy stands as a revolutionary approach in medicine, aiming to rectify genetic abnormalities by introducing therapeutic genes or regulating gene expression. This chapter encapsulates the current state-of-the-art advancements in gene therapy, focusing on the utilization of nanodelivery systems for precise and efficient gene transfer. The primary modalities in gene therapy encompass viral vector-mediated gene therapy, non-viral gene therapy, and genome editing techniques. Viral vector-mediated gene therapy utilizes genetically engineered viruses to deliver therapeutic genes, while nonviral gene therapy employs naked DNA or RNA molecules. Furthermore, genome editing enables the direct manipulation of a patient’s genome to rectify disease-causing DNA sequences. However, challenges persist in gene therapy, including immune responses triggered by viral vectors, limiting therapeutic efficacy. To mitigate these challenges, researchers are actively engineering less immunogenic vectors and exploring the synergistic use of immunosuppressive drugs. Recent advancements have witnessed the emergence of nanodelivery systems as promising alternatives for gene transfer. These systems, including cationic polymers, lipid nanoparticles, dendrimers, and inorganic nanoparticles, offer enhanced gene transfer efficiency and improved safety profiles. Notably, polymersomes, synthetic vesicles with heightened stability and cargo retention, exhibit potential for delivering therapeutic agents to the cytosol with precision. Targeting strategies play a pivotal role in ensuring the precise delivery of therapeutic genes to desired sites within the body. Passive and active targeting mechanisms, ligand-receptor interactions, and stimulus-responsive techniques are being harnessed to enhance targeting efficiency, thereby augmenting the therapeutic efficacy of gene therapy. Clinical studies and trials have underscored the promising outcomes of nanodelivery systems in gene therapy across various diseases. From liver cancer to cystic fibrosis and head and neck squamous cell carcinoma, nanodelivery systems have exhibited notable efficacy in tumor regression, improved lung function, and minimal side effects. In conclusion, nanodelivery systems represent a burgeoning frontier in gene therapy, offering unparalleled precision and efficacy in delivering therapeutic genes. Continued research endeavors aimed at refining nanocarrier design and targeting strategies hold immense promise for the future of precision medicine, paving the way for transformative advancements in the treatment of diverse diseases and conditions.