The severity of bone loss that results from mechanical unloading is dependent, in part, on genetic variations, and identifying the mechanisms by which genetics modulate bone’s mechanosensitivity will be critical for developing appropriate diagnostic tools and treatments. Unloading studies using genetically distinct strains of female mice suggest strain-specific differences in bone’s architectural, cellular, and molecular level responses to disuse, and comparisons with unloading studies using males suggests a complex interaction by which genetics and gender modulate bone’s architectural level response to unloading. The overall hypothesis of this dissertation was that genetics and gender will modulate bone’s response to unloading at the architectural, cellular, and transcriptional levels. Direct gender comparisons made from an unloading study using males and females from the same genetic background revealed that the unloading effects on bone quantity were gender-dependent and that the magnitude of the effects varied across anatomic sites within a given bone and across distinct bones. Furthermore, the skeleton’s gender- and site-specific sensitivity to unloading may be explained, at least in part, by baseline bone morphology and indices of bone formation. Investigating the cellular and molecular bases of disuse-induced changes in the skeletons of genetically distinct strains of male mice revealed strain-specific differences in the magnitude of disuse-induced changes in gene expression and indices of bone formation, yet the loss of bone quantity was similar across the strains. Finally, microarray analyses identified differentially expressed genes with functions ranging from protein kinases, to DNA transcription factors, regulators of the cell cycle, and apoptosis;​ however none of the candidate bone genes were affected by unloading suggesting that some of the other genes identified play important roles in regulating bone’s response to unloading. Future analyses of some o f these genes may lead to the identification o f novel genes with functions in regulating skeletal mechanosensitivity. If extrapolation to humans is appropriate, these findings provide additional support that complex interactions between genetics, gender, and the specific anatomic site that is being examined influence bone’s response to unloading at the architectural, cellular, and molecular level and that diagnostic and therapeutic tools will need to consider these factors.