Most men with advanced prostate cancer have primarily skeletal metastases, which are responsible for most of the morbidity and mortality of prostate cancer. Although bone lesions are osteoblastic in radiographic appearance, recent evidence has demonstrated that anti-osteoclast therapy with bisphosphonates reduces skeletal-related complications in hormone-refractory prostate cancer. This observation may be explained by the demonstration that osteoclast activity is greatly upregulated even in osteoblastic metastases. Furthermore, androgen deprivation therapy, the mainstay of treatment for advanced prostate cancer, leads to increased bone resorption and reduces bone mineral density. These effects can be ameliorated, and potentially completely prevented, by coadministration of bisphosphonates. These findings may point to a role for bisphosphonates in men with prostate cancer even prior to the development of skeletal metastases. Determination of whether such early therapy ultimately results in delayed time to skeletal progression or in improved survival will require large randomized studies.