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Research in regenerative medicine is thriving across the world, and América del Sur is no exception. This special issue of Gene Therapy, coordinated by South America Associate Editor Ursula da Silveira Matte and Guest Editor Hugo Peluffo Zavala, is devoted to work submitted by authors located in many South American countries, with topics including cancer, cardiovascular, Parkinson and inherited diseases. The papers report use of multiple gene and cell therapy technologies, spanning viral and non-viral vectors, genome editing, DNA vaccines, chimeric antigen receptor T-cells (CAR-T), induced pluripotent stem cells (iPSC), and adipose-tissue-derived stem cells.