Bone metastases are a frequent and devastating complication in cancer patients. Recently, significant advances in our understanding of the molecular mechanisms responsible for both osteolytic and osteoblastic bone metastases have occurred. The use of OMICS and the availability of appropriate preclinical animal models of bone metastasis have permitted the identification of factors produced by the tumor or by the host stroma in response to the tumor. These types of studies should result in a decrease of the serious skeletal morbidities associated with metastatic prostate cancer and may in the future improve overall survival. In this review the next generation of molecular targets in bone metastasis will be summarized.