Glucocorticoids (GCs) are commonly used in the treatment of hematopoietic malignancies owing to their ability to induce apoptosis of these cancerous cells. Whereas some types of lymphoma and leukemia respond well to this drug, others are resistant. Also, GC-resistance gradually develops upon repeated treatments ultimately leading to refractory relapsed disease. Understanding the mechanisms regulating GC-induced apoptosis is therefore uttermost important for designing novel treatment strategies that overcome GC-resistance. This review discusses updated data describing the complex regulation of the cell's susceptibility to apoptosis triggered by GCs. We address both the genomic and nongenomic effects involved in promoting the apoptotic signals as well as the resistance mechanisms opposing these signals. Eventually we address potential strategies of clinical relevance that sensitize GC-resistant lymphoma and leukemia cells to this drug. The major target is the nongenomic signal transduction machinery where the interplay between protein kinases determines the cell fate. Shifting the balance of the kinome towards a state where Glycogen synthase kinase 3α (GSK3α) is kept active, favors an apoptotic response. Accumulating data show that it is possible to therapeutically modulate GC-resistance in patients, thereby improving the response to GC therapy.