A broadly held view of bone is that it is a tissue defined by its mechanical and scaffolding properties, whose interaction with other organs of the body is similar to that exerted by an armor protecting them. In the last 10 years, using mouse genetics, this view of bone as an assembly of inert calcified tubes has considerably evolved to a much more dynamic picture. It is now clear that the skeleton is not a simple target tissue for the hormones secreted by other organs, but it is an endocrine organ itself. Genetics and biochemical evidence have established that osteocalcin, an osteoblast-derived hormone, is an endocrine regulator of energy metabolism and male fertility. These novel hormonal connections between bone, energy metabolism, and reproduction underscore the concept of functional dependence in physiology and the importance of genetic approaches to identify novel endocrine regulations.