The past decade has witnessed a major increase in our knowledge of bone matrix proteins. These advances stem from investigations of genetically altered mice and the phenotypic analysis of the consequences of the deletion of these proteins. Surprisingly, however, some genes expected to yield considerable phenotypes because of their specificity for bone--for example, osteocalcin--exhibit only subtle changes. A picture is beginning to emerge that suggests important interactions between matrix proteins and other molecules in the bone environment, cytokines, cell surface receptors, growth factors, and other matrix proteins. Future studies require investigation of downstream events of protein ablation and require investment in microarray and proteomics. Double and triple deletions of relevant bone proteins may provide further insight into the function of these important components of bone and lead to new therapeutics for the treatment of osteoporosis and other metabolic bone diseases.