The skeleton is a multifunctional organ system that serves several vital roles in the body. Although bone has the ability to remodel itself to repair damage and respond to calcium demands, it is subject to the rigors of aging, hormonal changes, and environment. Understanding the mechanisms that cause bone loss is an important facet of human medicine. Animal models permit mechanistic study of processes that regulate development and maintenance of skeletal mass, enabling meticulous investigation of new orthopedic strategies or bone-targeted pharmacologic therapies. The selection of an appropriate animal model, choice of skeletal analysis techniques, and proper interpretation of data are vital components of experimental design and analysis in bone research. In this chapter, we review time-tested criteria for choosing appropriate animal models, describe several common animal models of osteoporosis, and summarize some of the basic methodology available for in vivo, ex vivo and in vitro analysis of skeletal biology.