THE primacy defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorption by osteoclasts(1). Osteoclasts express high levels of the c-Src protein(2,3) and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src(-)) mouse is fell-autonomous and occurs in mature osteoclasts(4,5). However, the specific signalling pathways that require c-Src expression for normal osteoclast activity have not been elucidated. We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some vesicular structures. In vitro bone resorption by osteoclast-like cells (OCLs) is inhibited by both c-src and c-cbl antisense oligonucleotides, Furthermore, tryosine phosphorylation of c-Cbl and the localization of c-Cbl-containing structures to the peripheral cytoskeleton are impaired in resorption-deficient c-src(-) OCLs, as well as in wild-type OCLs that have been treated with c-src antisense oligonucleotides. These results indicate that c-Cbl may act downstream of c-Src in a signalling pathway that is required for bone resorption.