In vitro stimulation of bone resorption was observed with the glucocorticoids hydrocortisone and dexamethasone. Dosage‐dependent release of ⁴⁵Ca from neonatal mouse calvarial bones was found for both steroids, with half‐maximal responses for hydrocortisone and dexamethasone of 0.3 and 0.08 μM, respectively. Significant release of stable calcium (Ca²⁺), inorganic phosphate (P_i), and the lysosomal enzyme β‐N‐acetylglucosaminidase was noted following treatment of mouse calvariae with either 1 μM hydrocortisone or 1 μM dexamethasone. Additionally, both 1 μM hydrocortisone and 1 μM dexamethasone elicited release of ³H from calvarial bones prelabeled with [³H]proline. The stimulation of bone resorption by the glucocorticoids, as assessed by ⁴⁵Ca release, was sustained over 120 h of culture. Inhibition of ⁴⁵Ca release from calvariae treated with either 1 μM hydrocortisone or 0.1 μM dexamethasone was observed with 0.01‐30 nM salmon calcitonin (sCT), 0.1 mM acetazolamide, and 0.1 mM of the bisphosphonate AHPrBP. Inhibition of glucocorticoid‐induced bone resorption by sCT occurred without “escape from calcitonin‐induced inhibition.” The ⁴⁵Ca release stimulated by 1 μM hydrocortisone and 0.1 μM dexamethasone was also inhibited by 10 μM progesterone in a competitive manner and by 1 μM of the antiglucocorticoid RU38486, both of which are modulators of glucocorticoid binding. Prostaglandin E₂ (PGE₂) formation by 10 nM parathyroid hormone (PTH) in neonatal mouse calvarial bones was inhibited by both 1 μM hydrocortisone and 1 μM dexamethasone, but neither compound altered basal PGE₂ formation. Exposure of calvarial bones to the mitotic inhibitors hydroxyurea and mitomycin C inhibited ⁴⁵Ca release stimulated by 1 μM hydrocortisone and 1 μM dexamethasone. In contrast, addition of 1 ng/ml of recombinant murine granulocyte macrophage colony stimulating factor (rmGM‐CSF) had no effect on ⁴⁵Ca release elicited by the glucocorticoids. These results suggest that hydrocortisone and dexamethasone stimulate osteoclastic resorption in neonatal mouse calvariae by a receptor‐mediated mechanism that is dependent on cellular replication.