Cancer is a major leading cause of death in the western world (following heart diseases). It poses an enormous burden on patients and society with a major impact on healthcare and economy. Once cancers have spread to the skeleton, treatment options are predominantly limited to palliation, treatment of hypercalcemia and prevention of pathological fractures. Despite the elaborate efforts of modern medicine to improve treatment, novel therapies for the treatment of solid tumors in patients with advanced disease, including metastatic bone disease, have generally failed to improve patient overall survival. Despite initial beneficial responses on metastatic tumor burden this is frequently followed by re-growth of therapy resistant, malignant metastatic bone lesions. Cancer relapse in bone coincides with devastating consequences and causes considerable morbidity. Bisphosphonates represent the current gold standard in bone metastasis therapies. Because of the progress made in our understanding of the pathogenesis of skeletal metastasis using preclinical models, newer and more efficacious compounds and therapies have been developed that are being evaluated (or will soon be) in clinical trails. In this chapter, we discuss novel therapeutic targets and strategies for the treatment of metastatic bone disease. Future, successful treatment of skeletal metastasis will rely on targeting critical molecular mediators/processes in both metastasis-initiating subpopulations of osteotropic cancers ("the seed") together with their supportive, cellular and extra-cellular surrounding bone/bone marrow stroma ("the soil").