Glucocorticoids (GCs) induce programmed cell death with the morphologic characteristics of apoptosis in cells of the lymphoid lineage at certain stages of differentiation. Although the physiological significance of this phenomenon is not well understood, it has been exploited to a great extent in the therapy of malignant lymphoproliferative disorders. In spite of its clinical importance, the molecular mechanisms underlying GC-induced apoptosis and – clinically even more important – resistance to this phenomenon are not known. This review summarizes efforts from our and other laboratories addressing these issues in human lymphoblastic leukemia, with particular emphasis on the CCRF-CEM childhood T-cell leukemia model. These studies have shed some light on the downstream execution phase of GC-induced apoptosis but the critical upstream gene regulatory events have remained a mystery. Very recent DNA chip-based expression profile analyses in our laboratory along with data from the literature have, however, suggested that GC receptor auto-upregulation in sensitive target cells might be the critical event leading to persistent downregulation of central metabolic pathways which is incompatible with cell survival. The validity of this hypothesis and its possible clinical implications are currently being investigated in our laboratory.