Age-related osteoporotic fractures are major health care problem worldwide and are the result of impaired bone formation, decreased bone mass and bone fragility. Bone formation is accomplished by skeletal stem cells (SSC) that are recruited to bone surfaces from bone marrow microenvironment. This review discusses targeting SSC to enhance bone formation and to abolish age-related bone fragility in the context of using stem cells for treatment of age-related disorders. Recent studies are presented that have demonstrated that SSC exhibit impaired functions during aging due to intrinsic senescence-related changes as well as the presence of senescent microenvironment. Also, a number of approaches aiming at increasing bone formation through targeting SSC and that include systemic SSC transplantation, systemic SSC targeting using aptamers or antibodies, use of therapeutic screteome and tissue engineering approaches will be presented and discussed. © 2015, The Author(s).