Cancer cells in the bone metastasis would acquire their characteristic malignant potentials by breaking through the struggle for existence in the various metastasis steps, all of which are required for the cancer cells in the bone microenvironment to emerge as clinical bone metastasis. We have demonstrated that receptor activator of NF-κB ligand (RANKL) was involved in the tumor-stromal interaction in the bone microenvironment and TGFβ stored in the bone matrix was released with the bone destruction, which promoted the proliferation of cancer cells in the bone. We also demonstrated that epigenetics, which is the transcriptional regulatory mechanism without gene mutation, was involved in the acquisition of drug resistance in the cancer cells. We believe that the mechanisms for bone metastasis formation would be fully elucidated in the near future, and the molecular-targeted therapies, which was developed based on these findings, would relief the patients from the fear of death.