Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has rapidly changed current treatment pattern, providing a better option for individuals with primary refractory or relapsed B-cell non-Hodgkin lymphoma (r/r B-NHL) and B-cell acute lymphoblastic leukemia (r/r B-ALL). However, despite the outstanding efficacy, a high relapse rate is still found in some B-cell malignancies after anti-CD19 CAR T-cell therapy, which emerges as a main barrier for improving the overall response and long-term outcomes. Understanding the resistance mechanism is crucial to improve current CAR T products, better incorporate them into the current therapy system and develop novel CAR approaches. Herein, we discuss the latest advances in understanding the mechanisms limiting efficacy of CAR T-cell therapy, resulting in CD19 negative (CD19- ) and CD19 positive (CD19+ ) relapses. We also provide a whole scenario of current potential strategies to overcome these barriers. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.