Simple SummaryAlthough remarkable progress in the treatment of acute lymphoblastic leukemia (ALL) has been observed, some patients (~20%) relapse. Resistance to therapies is a hallmark of relapses and treatment failure in ALL. Such resistances may involve different cellular mechanisms, including the modulation by therapeutic drugs of cell survival signaling pathways that may lead to therapy-induced resistance. This article will begin by providing an update of mechanisms of resistance that may lead to therapy-induced resistance in ALL. It also provides proof of concept for the therapeutic exploitation of these signaling pathways to improve treatments.AbstractKnown as a key effector in relapse of acute lymphoblastic leukemia (ALL), resistance to drug-induced apoptosis, is tightly considered one of the main prognostic factors for the disease. ALL cells are constantly developing cellular strategies to survive and resist therapeutic drugs. Glucocorticoids (GCs) are one of the most important agents used in the treatment of ALL due to their ability to induce cell death. The mechanisms of GC resistance of ALL cells are largely unknown and intense research is currently focused on this topic. Such resistance can involve different cellular and molecular mechanisms, including the modulation of signaling pathways involved in the regulation of proliferation, apoptosis, autophagy, metabolism, epigenetic modifications and tumor suppressors. Recently, several studies point to the paradoxical role of GCs in many survival processes that may lead to therapy-induced resistance in ALL cells, which we called “paradoxical corticosensitivity”. In this review, we aim to summarize all findings on cell survival pathways paradoxically activated by GCs with an emphasis on previous and current knowledge on gene expression and signaling pathways.