In this chapter currently available preclinical models of tumor progression and bone metastasis, including genetically engineered mice that develop primary and metastatic carcinomas and transplantable animal models, will be described. Understanding the multistep process of incurable bone metastasis is pivotal to the development of new therapeutic strategies. Novel technologies for imaging molecules or pathologic processes in cancers and their surrounding stroma have emerged rapidly and have greatly facilitated cancer research, in particular the cellular behavior of osteotropic tumors and their response to new and existing therapeutic agents. Optical imaging, in particular, has become an important tool in preclinical bone metastasis models, clinical trials and medical practice. Advances in experimental and clinical imaging will-in the long run-result in significant improvements in diagnosis, tumor localization, enhanced drug delivery and treatment.