The division of labor among cells of the skeleton is distinct and diverse and the regulation of these cells is interdependent. Osteoclasts are the cellular source of bone resorption and signals for their development and activation come, at least in part, from bone and other cells in the local environment. Studies of isolated cells have identified some factors in the developmental cascade of osteoclasts but there is little understanding of the sequence and local concentrations, not to mention other factors, needed for both the development of competent osteoclasts and for coordinated bone resorption. We review the skeletal biology of one osteopetrotic mutation in the rat, toothless, in which bone resorption is severely reduced because of a failure in the development and function of osteoclasts. Furthermore, we review the advantages and limitations of a relatively new method, differential display of mRNA (DD), that identifies differences in gene expression in two or more populations of cells. We present a strategy and preliminary data for the application of DD to this mutation. We propose that application of this method to these and other skeletal diseases, with the appropriate controls and confirmations, will provide data about pathogenetic pathways and has a high probability for identifying new regulators of skeletal development and turnover.