Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment by offering personalized immunotherapy against hematologic malignancies and solid tumors. Despite its remarkable efficacy, CAR T-cell therapy is connected to severe adverse impacts, primarily cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which display significant clinical challenges. CRS results from excessive cytokine production, leading to systemic inflammation, multi-organ dysfunction, and, in severe cases, life-threatening complications. ICANS manifests as neurotoxicity ranging from mild confusion to seizures and cerebral edema, necessitating careful neurological monitoring. The incidence and severity of these toxicities vary across cancer types, with higher risks observed in hematopoietic cancers, including acute lymphoblastic leukemia and B-cell lymphomas. Effective management strategies involve graded assessment scales, corticosteroid therapy, IL-6/IL-1 inhibitors, and intensive supportive care to mitigate toxicity without compromising therapeutic efficacy. Additionally, emerging evidence suggests that gut microbiota modulation may play a pivotal role in managing CAR T-cell-related adverse effects by influencing immune homeostasis and inflammatory responses. This chapter comprehensively explores the adverse effects of CAR T-cell therapy, their association with different cancers, clinical management approaches, and the possible contribution of gut microbiota to toxicity reduction, opening the door to safer and more efficient immunotherapeutic treatments.