Regenerative medicine is a high-potential sector of strategic developments in medicine and health industry. The perspective to cure diseases up to now relied on medical treatments of long duration and limited effectiveness, and the possibility to avoid organ transplantation renders regenerative medicine attractive. In recent years, basic and translation research held great hope for this new field with significant progress in the modulation of stem cell commitment in vitro and providing protocols for targeted clinical applications. In line with this approach, mesenchymal stem cells (MSCs) have been introduced as potential therapeutic tools to correct the breakdown of musculoskeletal disorders. MSCs are able to secrete a large number of trophic factors capable of repairing the recipient tissue through angiogenic, anti-apoptotic and anti-fibrotic mechanisms. In this context, adipose tissue is emerging as a clinically relevant and easy to harvest source of multipotent progenitors to develop regenerative therapies. The present review focuses on the clinical application of MSCs, and in particular of adipose-derived stem cells, in the musculoskeletal disorders and on the current scientific challenges. In this perspective, we discuss future developments of an innovative system (Lipogems) for musculoskeletal regeneration, yielding a non-expanded and ready-to- use microfractured fat tissue product harbouring MSCs and pericytes within a preserved stromal vascular niche. The Lipogems system may also pave the way for future off-the-shelf and large-scale approaches for reconstructive procedures and regenerative medicine.