Bone metastases are a late event in tumor progression, contributing to morbidity and mortality and decreasing patient quality of life. Cancer colonization of the skeleton is characteristic of advanced tumors of breast, prostate and other sites and of multiple myeloma. The pathophysiology of cancer in the skeleton can be conceptualized as a vicious cycle, where cancer-secreted factors activate bone cells to release factors that encourage further growth of tumor, which in turn secretes more factors into the microenvironment. Bone provides unusual physical conditions favorable to tumor growth: low pH and oxygen tension and high concentrations of calcium, phosphate and many growth factors. It also houses stem cells, bone marrow and immune cells, which can encourage the establishment, growth and survival of metastases. A plethora of bone and tumor factors contributes to the vicious cycle: too many to be individually targeted in the clinic. However, inhibition of bone resorption is invariably effective and may oppose the initial development of cancer in bone. Central pathways, such as hypoxia and TGFβ signaling, are important for both tumor and bone functions; they are promising targets for improved therapies, while other pathways may yield future treatments to decrease bone metastases and myeloma bone disease.