The advent of chimeric antigen receptor (CAR)-T cell therapy has been hailed as a major breakthrough in the treatment of B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). While multiple promising CAR-T cell clinical trials continue to receive approval from the FDA and the Chinese Clinical Trial Register (ChiCTR), many hematologic malignancies patients nonetheless experience disease relapse following treatment as a consequence of genetic mutations, antigen escape, lineage switching, poor CAR-T cell persistence, CAR T cell exhaustion, and immunogenicity against CAR T cells. In this article, we summarize the structural characteristics of CAR constructs and discuss clinical factors known to be related to relapse following CAR-T cell treatment. By better understanding the mechanistic basis for such disease recurrence, it will be possible to fully realize the potential of this potent therapeutic modality in the future. This review will focus on current activate strategies aimed at overcoming known limitations to CAR-T cell therapy in an effort to improve hematologic malignancies patient outcomes.