A review outlines recent advances in mitochondrial gene therapy and the technical and translational challenges that remain. Authors summarized novel delivery systems, genome editing tools targeting mitochondrial DNA (mtDNA), and preclinical successes while calling attention to hurdles such as heteroplasmy, tissue delivery barriers, and immune responses. The review maps regulatory and manufacturing bottlenecks and recommends standardized assays for on‑target and off‑target effects to move therapies toward clinical trials. For readers: heteroplasmy is the coexistence of mutated and wild‑type mtDNA within cells, a core challenge for mtDNA correction strategies.