Although glucocorticoids (GCs) have been used for their immunosuppressive, anti-inflammatory, and cytotoxic effects for many years, their precise mechanism of action has not been fully elucidated. Evidence indicates that GCs induce apoptosis in hematological cells, thus supporting their use as chemotherapeutic agents for leukemias, lymphomas, and myeloma. Although much research has been focused on investigating the mechanism of action responsible for GC-mediated cell death, the signaling pathways remain unclear. Two schools of thought have developed to account for GC-induced apoptosis. One supports the hypothesis that apoptosis is achieved via activation of death-inducing genes. The second theory states that GCs induce apoptosis via repression of transcription factor activity, thereby inhibiting the transcription of growth/survival genes. This review will attempt to clarify the complex signaling pathway responsible for mediating GC-induced apoptosis of hematological cells and to summarize the most current research in this field.