The immunotherapy revolution in hematologic malignancies involves synthetic immunology – the generation of novel immune responses through bispecific T-cell engagers and chimeric-antigen-receptor (CAR)-T cells. In the past 5 years, CAR T cells have evolved from promising small academic clinical trials in heavily-pretreated patients into FDA and EMA approved products. The use of these modalities entails complexity, given that the starting product is produces by the medical centers, the duration of production, and the unique toxicities seen after this therapy. Also, despite high rates of remission, resistance to these cells and relapse do occur. Through studying the mechanisms of relapse, we can better define future challenges in designing CAR T Cells and incorporating them in standard treatment regimens for patients.