Although the primary roles of osteoblasts are to synthesize the components of bone matrix and to regulate the activity of bone resorbing osteoclasts, there is growing realization that osteoblasts have an additional function during bone diseases, such as osteomyelitis. Based on our recent studies, we propose a novel role for osteoblasts during bacterial infections of bone, namely, the initiation and maintenance of inflammatory immune responses. In this article, we describe how these nonleukocytic cells can perceive bacterial pathogens of bone to initiate the production of an array of immune regulatory molecules. This pattern of expression is one that could promote the recruitment of leukocytes to sites of bacterial challenge, initiate antigen-specific activation of infiltrating cells, and facilitate the development of cell-mediated host responses to intracellular pathogens of bone tissue, thereby identifying this cell type as a previously unappreciated component in host responses.