Chimeric antigen receptor T-cell (CAR-T) therapies have transformed the treatment of several hematologic malignancies, offering a powerful new option for patients with otherwise refractory cancers. Despite their groundbreaking success, these therapies are associated with a range of toxicities, including cytokine-release syndrome (CRS), neurological toxicities (ICANS), hematologic, and organ-specific adverse effects, along with immune-related adverse events (IRAEs). Understanding and managing these toxicities is critical for optimizing patient outcomes and expanding the use of CAR T-cell therapies. This chapter offers a broad overview of the mechanisms underlying CAR T-cell-related toxicity, highlighting the importance of a proactive and structured approach to toxicity management. The discussion includes an in-depth analysis of CRS and neurological toxicities, detailing their pathophysiology, clinical presentation, risk factors, and current management strategies. Additionally, the chapter covers hematologic, hepatic, pulmonary, renal, and immunogenic toxicities, emphasizing the need for vigilant monitoring and timely intervention. To mitigate these toxicities, this chapter outlines key strategies, such as pretreatment risk assessment, patient education, and innovations in CAR T-cell manufacturing. Furthermore, novel approaches and adjunct therapies designed to reduce the severity of adverse events without compromising therapeutic efficacy have been explored. Integrating these advancements into clinical practices can increase the safety and effectiveness of CAR T-cell therapies, ultimately improving patient care and expanding the potential applications of this transformative treatment.