The ability of glucocorticoids (GC) to efficiently kill lymphoid cells has led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies. This review summarizes recent findings related to the molecular basis of GC-induced apoptosis and GC resistance, and discusses their potential clinical implications. Accumulating evidence suggests that GC may induce cell death via different pathways resulting in apoptotic or necrotic morphologies, depending on the availability/responsiveness of the apoptotic machinery. The former might result from regulation of typical apoptosis genes such as members of the Bcl-2 family, the latter from detrimental GC effects on essential cellular functions possibly perpetuated by GC receptor (GR) autoinduction. Although other possibilities exist, GC resistance might frequently result from defective GR expression, perhaps the most efficient means to target multiple antileukemic GC effects. Numerous novel drug combinations are currently being tested to prevent resistance and improve GC efficacy in the therapy of lymphoid malignancies.