Exciting discoveries over the last years have propelled osteocytes, originally considered passive and metabolically inactive bone cells, to the category of master regulators of bone homeostasis. Osteocytes differentiate from osteoblasts when they become surrounded by matrix during the process of bone formation. Osteoblast to osteocyte differentiation is complex and involves profound modifications in gene expression that result in morphological changes and transform osteocytes in dynamic and multifunctional cells. In addition to the traditional role of osteocytes in the integration of mechanical signals, new osteocytic functions are emerging. Osteocytes are now considered a major source of molecules that coordinate the activity of osteoclasts and osteoblasts in response to both physical and hormonal cues. In addition, accumulating evidence supports the notion that dysregulation of osteocyte function underlies the pathophysiology of several skeletal disorders, ranging from rare to common diseases such as osteoporosis. Further, the increased understanding of osteocyte biology has led to the development of therapeutic approaches targeting osteocytes and their derived factors. In this chapter, we summarize the current knowledge on osteocyte biology and its different functions and discuss novel observations that support the role of osteocytes as endocrine regulators of body composition and energy metabolism and as key players in the deleterious effects of cancer and diabetes on bone.