Mesenchymal stem cells (MSCs) have been shown to be perivascular in vivo, suggesting they play a broader role than previously thought as cellular modulators. MSCs are released from their perivascular location during local injury, become activated, and establish a regenerative microenvironment by secreting bioactive molecules and regulating the local immune response. These trophic and immunomodulatory activities suggest that MSCs may serve as site-regulated "drugstores" in vivo. MSCs originate from the mesodermal layer during embryonic development and can differentiate into various mesenchymal tissues. In adult bone marrow, MSCs are thought to give rise to a spectrum of mesenchymal tissues through distinct lineage pathways. MSCs have been isolated and cultured from adult human bone marrow, showing multipotency for mesenchymal differentiation. This has led to their use in tissue engineering to replace or repair damaged mesenchymal tissues. The focus on MSCs' multipotency and tissue engineering has overshadowed their natural functions in bone marrow and other tissues. MSCs can support hematopoiesis in culture and are considered part of the supportive bone marrow stroma. Early clinical trials used MSCs to augment bone marrow transplantation for cancer patients. MSCs are also called "multipotential mesenchymal stromal cells" or "marrow stromal cells," but the term "MSC" is preferred. MSCs exhibit stemness properties, including self-renewal and multipotential differentiation, and can be isolated from nonparenchymal components of various tissues. This logic applies to other tissue-derived cells, such as adipose-derived stem cells. MSCs are pericytes, located in perivascular locations, and exhibit similar cell surface markers to MSCs. They can be isolated from any vascularized tissue and secrete large quantities of bioactive molecules as part of their local trophic and immunomodulatory activities. These activities suggest that MSCs serve as site-regulated "drugstores" in vivo, secreting bioactive molecules to inhibit immune cell activity and promote tissue regeneration. MSCs have shown therapeutic benefits in preclinical studies and clinical trials for various conditions, including bone marrow transplantation, graft versus host disease, acute myocardial infarct, stroke, spinal cord injury, lung disease, acute kidney failure, liver fibrosis, tendinitis, juvenile diabetes, radiation syndrome, burns, wound healing, osteoarthritis, rheumatoid arthritis, lupus, autism, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis, urinary incontinence, and sepsis. These benefits are attributed to immunomodulation and trophic activities. MSCs also produce antimicrobial peptides, such as hCAP-18/LL37, which can combat both gram-positive and gram-negative bacteria. This suggests that MSCs may be useful in treating local and disseminated infectionsMesenchymal stem cells (MSCs) have been shown to be perivascular in vivo, suggesting they play a broader role than previously thought as cellular modulators. MSCs are released from their perivascular location during local injury, become activated, and establish a regenerative microenvironment by secreting bioactive molecules and regulating the local immune response. These trophic and immunomodulatory activities suggest that MSCs may serve as site-regulated "drugstores" in vivo. MSCs originate from the mesodermal layer during embryonic development and can differentiate into various mesenchymal tissues. In adult bone marrow, MSCs are thought to give rise to a spectrum of mesenchymal tissues through distinct lineage pathways. MSCs have been isolated and cultured from adult human bone marrow, showing multipotency for mesenchymal differentiation. This has led to their use in tissue engineering to replace or repair damaged mesenchymal tissues. The focus on MSCs' multipotency and tissue engineering has overshadowed their natural functions in bone marrow and other tissues. MSCs can support hematopoiesis in culture and are considered part of the supportive bone marrow stroma. Early clinical trials used MSCs to augment bone marrow transplantation for cancer patients. MSCs are also called "multipotential mesenchymal stromal cells" or "marrow stromal cells," but the term "MSC" is preferred. MSCs exhibit stemness properties, including self-renewal and multipotential differentiation, and can be isolated from nonparenchymal components of various tissues. This logic applies to other tissue-derived cells, such as adipose-derived stem cells. MSCs are pericytes, located in perivascular locations, and exhibit similar cell surface markers to MSCs. They can be isolated from any vascularized tissue and secrete large quantities of bioactive molecules as part of their local trophic and immunomodulatory activities. These activities suggest that MSCs serve as site-regulated "drugstores" in vivo, secreting bioactive molecules to inhibit immune cell activity and promote tissue regeneration. MSCs have shown therapeutic benefits in preclinical studies and clinical trials for various conditions, including bone marrow transplantation, graft versus host disease, acute myocardial infarct, stroke, spinal cord injury, lung disease, acute kidney failure, liver fibrosis, tendinitis, juvenile diabetes, radiation syndrome, burns, wound healing, osteoarthritis, rheumatoid arthritis, lupus, autism, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis, urinary incontinence, and sepsis. These benefits are attributed to immunomodulation and trophic activities. MSCs also produce antimicrobial peptides, such as hCAP-18/LL37, which can combat both gram-positive and gram-negative bacteria. This suggests that MSCs may be useful in treating local and disseminated infections