The availability of high-throughput biochemical and imaging techniques that can be used on live mice has increased the possibility of undertaking longitudinal studies to characterize skeletal changes such as bone mineral content and density. Further characterization of bone morphology, bone quality, and bone strength can also be achieved by analyzing dissected bones using techniques that provide higher resolution. Thus, the combined use of high-throughput [e.g., biochemical analysis of plasma, radiography and dual-energy X-ray absorptiometry (DEXA)] and secondary phenotyping techniques (e.g., histology, histomorphometry, Faxitron digital X-ray point projection microradiography, biomechanical testing, and micro-computed tomography) can be utilized for comprehensive characterization of bone structure and quality and to elucidate the underlying molecular mechanisms giving rise to musculoskeletal disorders. Curr. Protoc. Mouse Biol. 2:365-400 © 2012 by John Wiley & Sons, Inc.