Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new form of immunotherapy for the treatment of hematologic malignancies. The two primary toxicities associated with CAR T-cell therapy include cytokine-release syndrome and neurotoxicity. Cytokine-release syndrome is generally self-limited but high-grade toxicities like hypotension and hypoxemia can be managed with agents that block the effects of IL-6, like tocilizumab, and/or corticosteroids. Although CAR T-cell therapy–associated neurotoxicity is a well-described clinical phenomenon, its pathophysiology remains inadequately understood; treatments and preventive strategies remain elusive. Animal models and clinical trial experience suggest the centrality of monocytes, endothelial dysfunction, and the blood-brain barrier in the development of CAR T-cell–associated neurotoxicity. Here we report what is known from preclinical models, clinical trials, and histopathologic studies regarding the pathophysiology of neurotoxicity, predictors of its incidence, and potential targets for the treatment and prevention of neurotoxicity.