Application of immunotherapeutic modalities changed paradigms in the treatment of hematologic malignancies, with regards to drug manufacturing, treatment protocols, short- and long-term toxicities. FDA-approved therapies, including blinatumomab, tisagenlecleucel, and axicabtagene ciloleucel, target T cells to attack healthy and malignant cells expressing CD19, leading to high response rates in previously heavily treated patients, and to durable remissions in the absence of further therapies. Nevertheless, despite paucity of long-term data, some patients are resistant to these agents, and many relapse. This review will discuss the mechanisms of failure of these immune-based therapies, and offer guidelines to the practicing physician.