Cytoskeletal organization of the osteoclast (OC), which is central to the capacity of the cell to resorb bone, is induced by occupancy of the alphavbeta3 integrin or the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. In both circumstances, the tyrosine kinase Syk is an essential signaling intermediary. We demonstrate that Cbl negatively regulates OC function by interacting with Syk(Y317). Expression of nonphosphorylatable Syk(Y317F) in primary Syk(-/-) OCs enhances M-CSF- and alphavbeta3-induced phosphorylation of the cytoskeleton-organizing molecules, SLP76, Vav3, and PLCgamma2, to levels greater than wild type, thereby accelerating the resorptive capacity of the cell. Syk(Y317) suppresses cytoskeletal organization and function while binding the ubiquitin-protein isopeptide ligase Cbl. Consequently, Syk(Y317F) abolishes M-CSF- and integrin-stimulated Syk ubiquitination. Thus, Cbl/Syk(Y317) association negatively regulates OC function and therefore is essential for maintenance of skeletal homeostasis.