Chimeric antigen receptor (CAR)-T cell therapy represents a paradigm shift in cancer treatment, especially in hematological malignancies. To date, three CAR-T cell products have received FDA-approval for clinical application, including axicabtagene ciloleucel for B-cell lymphoma, tisagenlecleucel for B-cell leukemia and lymphoma, and brexucabtagene autoleucel for mantle cell lymphoma. This groundbreaking success has stimulated exponentially increasing preclinical researches and clinical investigations of CAR-T cell therapy. Nevertheless, toxicities associated with CAR-T cell therapy are common and can be fatal, hampering its widespread use. With more optimized CAR-T cells being developed and tested, rational evaluation and scientific management of the relevant toxicities is urgently needed to ensure their safe use and clinical benefit for the patients. From a clinician’s perspective, this review summarizes prominent CAR-T cell-related toxicities and the road to safer CAR-T cell immunotherapies in the following three aspects: patient selection, CAR-T intrinsic factors, and post-infusion monitoring.