Bone is the most common site for metastasis of advanced prostate cancers. Once housed in the skeleton, tumors are incurable and cause protracted morbidity, and bone metastases may contribute to mortality through unknown mechanisms. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Many standard cancer treatments cause bone loss, which may aggravate skeletal metastases, although this is preventable with approved agents. Improved bone-targeted treatments can decrease the serious skeletal morbidities associated with metastatic prostate cancer and may in the future improve overall survival. The development of such treatments requires preclinical evaluation in animal models of prostate cancer growth in bone.