Advances in gene therapy and exosome research have unveiled promising opportunities for repairing and regenerating injured tissues in different body regions, including the musculoskeletal system. This chapter explores the multifaceted roles of exosomes, highlighting their importance as essential mediators in intercellular communication and their potential to act as signalling molecules. MicroRNAs, encapsulated within exosomes, play a major role in exosome-mediated function and are being studied as potent regulators that coordinate cellular processes that are necessary for musculoskeletal regeneration. Gene therapy has also been widely investigated in the regeneration of the musculoskeletal system; however, there is no consensus regarding the adequate vector, method of application, or approach. This chapter will also talk about the therapeutic potential of engineered exosomes, which involves genetic manipulation and using the transformative properties of exosomes to deal with the problems that come up with musculoskeletal repair. Nevertheless, the remaining issues and questions surrounding exosomes and gene therapy implementation in clinical practice must be resolved in combination with developing new guidelines for clinical use.