Bone formation is enhanced by mechanical loading, but human exercise intervention studies have shown that the response to mechanical loading is variable, with some individuals exhibiting robust osteogenic responses while others respond modestly. Thus, mechanosensitivity — the ability of bone tissue to detect mechanical loads — could be under genetic control. We applied controlled mechanical loading to the ulnae of 20-week-old (adult) female mice derived from three different inbred strains (C3H/He, C57BL/6, and DBA/2), and measured the bone formation response with fluorochrome labels. Mechanical properties, including mechanical strain, second moments of area, and cortical bone material properties, were measured in a group of calibration animals not subjected to in vivo loading. The C3H/He mice were significantly less responsive to mechanical loading than the other two biological strains. Material properties (flexural elastic modulus, ultimate stress) were greatest in the C3H/He cortical tissue. Geometric and areal properties at the midshaft ulna were also greatest in the C3H/He mice. Based on the presumed role of osteocytes in strain detection, we measured osteocyte lacuna population densities in decalcified midshaft ulna sections. Osteocyte lacuna density was not related to mechanosensitivity. Our data suggest that bone mechanosensitivity has a significant genetic component. Identification of the genes that exert their influence on mechanosensitivity could ultimately lead to therapies that enhance bone mass and reduce fracture susceptibility.