Probably the most striking example of musculoskeletal regeneration is the growing of an entire limb by a salamander, after it is traumatically amputated. This classic example unfortunately doesn't apply to humans, but (local) stem cells are indispensable in providing a renewable cell source for physiological tissue homeostasis and regeneration after musculoskeletal tissue injury. Stem cells have been isolated from the following musculoskeletal tissues: bone marrow, adipose tissue, periosteum, perichondrium, tendons, ligaments, muscle, cartilage, bone and synovial membrane or -fluid. We chose to refer to these cells as mesenchymal progenitor cells (MPCs). Cells from these different tissues are generally isolated by mincing the tissue followed by enzymatic digestion. Overall, the cells are positive for CD44, CD90, CD105 (CD146), CD166 and STRO-1 and negative for CD31, CD34, CD45 and CD117. On the whole, cell yields from these tissues and proliferation capacities of these cells appear to be within the same order of magnitude. Cells derived from the various musculoskeletal tissues have all been shown to have a multi-lineage differentiation potential, although they do show differentiation preferences, in general for differentiating towards the tissue they were originally derived from. Regenerative capacities of local stem cells are based on two characteristics. In the first place, they have the ability to differentiate into mature tissue cells, thereby contributing to new tissue formation. As a second quality, local stem cells secrete trophic factors that may be responsible for another mechanism of stem cell-mediated tissue repair. These trophic factors are capable of attracting (more) stem cells to the damaged area and they can play an immunomodulatory role. Musculoskeletal stem cells posses a huge capacity for application in regenerative medicine.