Periosteum contains osteogenic cells that regulate the outer shape of bone and work in coordination with inner cortical endosteum to regulate cortical thickness and the size and position of a bone in space. Induction of periosteal expansion, especially at sites such as the lumbar spine and femoral neck, reduces fracture risk by modifying bone dimensions to increase bone strength. The cell and molecular mechanisms that selectively and specifically activate periosteal expansion, as well as the mechanisms by which osteoporosis drugs regulate periosteum, remain poorly understood. We speculate that an alternate strategy to protect human bones from fracture may be through targeting of the periosteum, either using current or novel agents. In this review, we highlight current concepts of periosteal cell biology, including their apparent differences from endosteal osteogenic cells, discuss the limited data regarding how the periosteal surface is regulated by currently approved osteoporosis drugs, and suggest one potential means through which targeting periosteum may be achieved. Improving our understanding of mechanisms controlling periosteal expansion will likely provide insights necessary to enhance current and develop novel interventions to further reduce the risk of osteoporotic fractures.