Mesenchymal stem cells (MSCs) are a rare heterogeneous population of multipotent cells that can be isolated from many different adult and fetal tissues. They exhibit the capacity to give rise to cells of multiple lineages and are defined by their phenotype and functional properties, such as spindle-shaped morphology, adherence to plastic, immune response modulation capacity, and multilineage differentiation potential. Accordingly, MSCs have a wide range of promising applications in the treatment of autoimmune diseases, tissue repair, and regeneration. Recent studies have shed some light on the exact identity and native distribution of MSCs, whereas controversial results are still being reported, indicating the need for further review on their definition and origin. In this article, we summarize the important progress and describe some of our own relevant work on the developmental definition of MSCs.