There are many lines of evidence indicating that mechanical stress regulates bone metabolism and promotes bone growth. BMP, Wnt, ERK1/2, and OPG/RANKL are the main molecules thought to regulate the effects of mechanical loading on bone formation. Recently, microRNAs were found to be involved in bone cell proliferation and differentiation, regulating the balance of bone formation and bone resorption. Emerging evidence indicates that microRNAs also participate in mechanical stress-mediated bone metabolism, and is associated with disuse induced osteoporosis or osteopenia. Mechanical stress is able to induce expression of microRNAs that modulate the expression of osteogenic and bone resorption factors, leading to the positive impact of mechanical stress on bone. This review discusses the emerging evidence implicating an important role for microRNAs in the mechanical stress response in bone cells, as well as the challenges of translating microRNA research into potential treatment. J. Cell. Physiol. 232: 1239–1245, 2017.