Abstract: Adoptive cellular immunotherapy, a novel treatment paradigm, has demonstrated clinical success in oncological diseases. In chimeric antigen receptor-modified T cell (CAR-T) therapy, genetic engineering techniques reprogram T cells to enable them to target and eliminate tumor cells in a non major histocompability complex (MHC)-restricted manner. Significant disease remission rates were achieved in B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin’s lymphoma (NHL), and multiple myeloma (MM), providing patients with refractory and recurring hematological malignancies with opportunities to be cured. Therefore, several commercialized CAR-T products have received approval for clinical application, opening up a new era of tumor immunotherapy. Nevertheless, the development of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and other complications pose a threat to the application of CAR-T therapy. In addition, some patients develop resistance to CAR-T treatment; thus, new strategies to optimize CAR-T cell therapy are necessary to enhance eradication of tumor cells from various aspects. In this article, we provide an overview of the clinical research of CAR-T cell therapies in hematological malignancies and summarize the main challenges in future CAR-T cell therapy to provide insights to researchers on the development of CAR-T basic study and clinical translational research.