It is widely recognized that several types of cancer, including breast, prostate and lung, display a preference for skeletal sites when they metastasize. The majority of advanced breast and prostate cancer patients have detectable skeletal metastases and these metastases are often associated with intractable pain and patient morbidity. Therefore, the metastasis of cancers to bone represents a serious clinical problem in orthopedic medicine. Our research focuses on the cellular interactions and reciprocal regulatory signals between tumor cells that seed bone and the bone itself. These interactions are central to the selective establishment of metastases at skeletal sites. Over the past few years we have developed a research approach that allows for the identification of important regulators of these interactions allowing us to better understand the why certain cancer preferentially metastasize to bone. For example, we have demonstrated that metastatic breast and prostate cancers express the transcription factor Runx2 and that disruption of Runx2 function in breast cancer cells abolishes their ability to grow and generate lesions in bone. These results suggest Runx2 plays a central role in the selective establishment of metastases at skeletal sites and we are currently directly testing this hypothesis. It is our hope that this research will advance our understanding of the process of metastasis and allow for the development of targeted therapeutic to treat the progression and metastasis of these cancers.