Chimeric antigen receptor (CAR) T cells (CART) therapies have changed and continue to change the treatment paradigms for B-cell malignancies because they can achieve durable complete remission in patients in whom multiple lines of treatment have failed. These unprecedented results have led to the widespread use of anti-CD19 CART therapy for patients with relapsed and refractory aggressive large B-cell lymphomas. While long-term follow-up data show that about one-third of patients achieve prolonged complete remission and are potentially cured, the majority of patients either do not respond to CD19 CART therapy or eventually relapse after CD19 CART therapy. These results are, on the one hand, driving intense research into identifying mechanisms of relapse and, on the other hand, inspiring the development of novel strategies to overcome resistance. This review summarizes current clinical outcomes of CART immunotherapy in B-cell non-Hodgkin lymphomas, describes the most up-to-date understanding of mechanisms of relapse and discusses novel strategies to address resistance to CART therapy. We are indeed at the beginning of a scientific trek to explore the mechanisms of resistance, seek out new, more effective treatment approaches based on these discoveries and to boldly go where no other therapy has gone before!