Lymphoid and leukemic cells are uniquely sensitive to the lytic actions of glucocorticoid hormones which activate a programmed cell death in these cells. The response to glucocorticoids is sensitive to modulations at each step of hormone action: cellular uptake, binding and activation of cytosolic receptors, nuclear translocation and transcriptional activity of the activated receptor and the expression levels of pro- and anti-apoptotic genes. This review, based mainly on our studies with leukemic cells in tissue culture and on clinical observations in childhood acute lymphoblastic leukemia, summarizes the potential impact of these checkpoints in the treatment of this disease. In addition, we will discuss interventions that may reverse resistance or promote sensitivity to apoptosis of leukemic cells by glucocorticoid hormones.