Sclerostin, a secreted protein encoded by the SOST gene, has been identified as a key regulator of bone formation by studies in human and mouse genetics. Expression of this protein in osteocytes has been shown to be regulated by mechanical forces, and this has been shown to be critical for the bone formation response to load. Osteocytic expression of sclerostin is also regulated by systemic hormones that are known to influence the skeleton including parathyroid hormone and calcitonin. Circulating levels of sclerostin appear to be influenced by circulating sex steroid levels. Paracrine and autocrine factors expressed by the cells within bone (osteoblasts, osteoclasts and osteocytes), including some members of the family of cytokines that signal through gp130 (oncostatin M, cardiotrophin-1 and leukemia inhibitory factor) as well as prostaglandin E 2, rapidly regulate osteocytic sclerostin expression, pointing to new paracrine networks within the bone matrix. In addition, regulation of sclerostin by osteoblastic transcription factors, such as osterix and zinc finger protein 467, has been identified. Finally, changes in sclerostin expression due to changes in osteoblast differentiation have been reported in response to inhibitors of ephrin signaling and in response to the inflammatory mediators tumor necrosis factor and TWEAK. This review will discuss the evidence for each of these influences and what they might mean for bone physiology.