Significance: Mechanosignaling is vital for maintaining the structural integrity of bone under physiologic conditions. These signals activate and suppress multiple signaling cascades regulating bone formation and resorption. Understanding these pathways is of prime importance to exploit their therapeutic potential in disorders associated with bone loss due to disuse, trauma, or disruption of homeostatic mechanisms. Recent Advances: In the case of cells of the bone, an impressive amount of data has been generated that provides evidence of a complex mechanism by which mechanical signals can maintain or disrupt cellular homeostasis by driving transcriptional regulation of growth factors, matrix proteins and inflammatory mediators in health and inflammation. Mechanical signals act on cells in a magnitude dependent manner to induce bone deposition or resorption. During health, physiological levels of these signals are essential for maintaining bone strength and architecture, whereas during inflammation, similar signals can curb inflammation by suppressing the nuclear factor kappa B (NF-κB) signaling cascade, while upregulating matrix synthesis via mothers against decapentaplegic homolog and/or Wnt signaling cascades. Contrarily, excessive mechanical forces can induce inflammation via activation of the NF-κB signaling cascade. Critical Issues: Given the osteogenic potential of mechanical signals, it is imperative to exploit their therapeutic efficacy for the treatment of bone disorders. Here we review select signaling pathways and mediators stimulated by mechanical signals to modulate the strength and integrity of the bone. Future Directions: Understanding the mechanisms of mechanotransduction and its effects on bone lay the groundwork for development of nonpharmacologic mechanostimulatory approaches for osteodegenerative diseases and optimal bone health. Antioxid. Redox Signal. 20, 970-985.