Both genetic and environmental factors are known to influence the structure of bone, contributing to its mechanical behavior during, and adaptive response to, loading. We introduce a novel approach to simultaneously address the genetically mediated, exercise-related effects on bone morphometrics and strength, using mice that had been selectively bred for high levels of voluntary wheel running (16 generations). Female mice from high-running and control lines were either allowed (n = 12, 12; respectively) or denied (n = 11, 12; respectively) access to wheels for 20 months. Femoral shaft, neck, and head were measured with calipers and via micro-computed tomography. Fracture characteristics of the femoral head were assessed in cantilever bending. After adjusting for variation in body mass by two-way analysis of covariance, distal width of the femur increased as a result of selective breeding, and mediolateral femoral diameter was reduced by wheel access. Cross-sectional area of the femoral mid-shaft showed a significant linetype × activity effect, increasing with wheel access in high-running lines but decreasing in control lines. Body mass was significantly positively correlated with many of the morphometric traits studied. Fracture load of the femoral neck was strongly positively predicted by morphometric traits of the femoral neck (r 2 > 0.30), but no significant effects of selective breeding or wheel access were found. The significant correlations of body mass with femoral morphometric traits underscore the importance of controlling for body size when analyzing the response of bone size and shape to experimental treatments. After controlling for body mass, measures of the femoral neck remain significant predictors of femoral neck strength.