The past decade has unraveled novel molecular mechanisms not only of skeletal remodeling, which is the process by which the skeleton is restructured throughout adult life, but also the precision by which the skeleton is put together during embryogenesis and later modeled during growth. It is now possible to delete single genes in individual cells and during specified periods of life. This has allowed us to pin down specific molecular events that underlie individual cellular processes, and also importantly, to identify molecular defects underlying disorders of skeletal morphogenesis and remodeling. Particularly novel has been the demonstration of cross-talk, some of which is humoral, between the skeleton and organs as diverse as the brain, pituitary, and even adipose tissue and pancreas. The current review describes these molecular mechanisms in relation to the way thyroid hormones, and the pituitary hormone thyrotropin (TSH), regulate skeletal morphogenesis and remodeling.