A key objective in regenerative medicine is the development of "off-the-shelf" cell therapies that combine reparative potential with a strong safety profile. Multilineage-differentiating stress-enduring (Muse) cells are an endogenous subpopulation of mesenchymal stem cells, primarily characterized by stage-specific embryonic antigen-3 (SSEA-3) positivity, non-tumorigenicity, and the potential for tri-lineage differentiation. Their reparative mechanisms involve homing to damaged tissues mediated by the sphingosine-1-phosphate and its receptor 2 (S1P-S1PR2) axis, rapid in situ differentiation via the phagocytosis of apoptotic cell fragments, and immune tolerance conferred by the expression of human leukocyte antigen-G. The safety profile of Muse cells is predicated on a unique molecular regulatory network that maintains pluripotency through the tumor suppressor let-7, rather than through oncogenes. Preclinical studies have corroborated their reparative efficacy in various injury models, including those of the neurological, cardiovascular, and hepatic systems, while early clinical trials have demonstrated their favorable safety profile across multiple diseases. Although the clinical translation of Muse cells continues to face challenges such as the rarity of cell sources, scalable manufacturing, and discrepancies between preclinical and clinical outcomes, "cell-free" therapies and strategies aimed at activating endogenous Muse cells serve as noteworthy directions for future development.