Glucocorticoids have been included in almost all treatment regimens for childhood acute lymphoblastic leukemia for decades. However, optimal agents, doses, and/or schedules have yet to be defined despite extensive clinical application. New data on the pharmacokinetics, pharmacodynamics, and molecular mechanisms of action of glucocorticoids have suggested alternative approaches in ALL. These suggest that prolonged, i.e. 28 day, glucocorticoid therapy may be unnecessary as exposure to glucocorticoid induces down-regulation of glucocorticoid receptors. Dexamethasone may be superior to prednisone in conventional equi-effective doses. Blast sensitivity to glucocorticoids correlates closely with sensitivity to other, putatively non-cross-resisting agents and with outcome after multi-agent therapy, suggesting overlapping mechanisms of action, and focusing attention on the determinants of the threshold for apoptosis. Increasing success in the treatment of childhood acute lymphoblastic leukemia has led to increasing awareness of avascular necrosis of bone as a potentially disabling sequela of glucocorticoid therapy, especially in adolescent and young adult patients.