Despite the rapid development of medicine, even nowadays, acute lymphoblastic leukemia (ALL) is still a problem for pediatric clinicians. Modern medicine has reached a limit of curability even though the recovery rate exceeds 90%. Relapse occurs in around 20% of treated patients and, regrettably, 10% of diagnosed ALL patients are still incurable. In this article, we would like to focus on the treatment resistance and disease relapse of patients with B-cell leukemia in the context of prognostic factors of ALL. We demonstrate the mechanisms of the resistance to steroid therapy and Tyrosine Kinase Inhibitors and assess the impact of genetic factors on the treatment resistance, especially TCF3::HLF translocation. We compare therapeutic protocols and decipher how cancer cells become resistant to innovative treatments—including CAR-T-cell therapies and monoclonal antibodies. The comparisons made in our article help to bring closer the main factors of resistance in hematologic malignancies in the context of ALL.