Cerebral malaria is a life-threatening complication of malaria caused by the parasite Plasmodium falciparum. The growing problem of drug resistance and the dearth of new antiparasitic drugs are a serious threat to the antimalaria treatment regimes. Studies on humans and the murine model have implicated the disruption of the blood-brain barrier (BBB) in the lethal course of the disease. Therefore, efforts to alleviate the BBB dysfunction could serve as an adjunct therapy. Here, we review the mechanisms associated with the disruption of the BBB. In addition, we discuss the current, still limited, knowledge on the contribution of different cell types, microparticles, and the kynurenine pathway in the regulation of BBB dysfunction, and how these molecules could be used as potential new therapeutic targets. Cerebral Malaria-Clinical Significance and the Differences between Murine and Human Studies Cerebral malaria (CM) is a severe neurological syndrome of human malaria caused by the parasite Plasmodium falciparum (Pf) affecting mainly children in sub-Saharan Africa and adults in Asia. The complications of CM include clouding of consciousness, cerebral seizures, and coma, and may lead to the death of the infected individual. According to the 2018 WHO World Malaria Report for 2017, 435 000 patients died of malaria, with CM accounting for 90% of the deaths. About a quarter of surviving patients suffer from long-term neurological and cognitive deficits such as behavioral abnormality, epilepsy, and impaired motor functions [1,2]. Over the years, quinine and artemisinin compounds (see Glossary) have been used for the treatment of severe malaria. The use of these drugs has led to the emergence of resistant strains [3,4]. The problem of drug resistance is ever growing, and novel therapeutic strategies need to be developed, particularly those targeting the host or host-pathogen interaction. Understanding the underlying mechanisms leading to the development of CM would aid in the identification of potential new therapeutic targets. One major limitation of human CM studies is that a detailed analysis of the intracerebral pathogenesis and pathology can be conducted mainly postmortem. Therefore, CM is experimentally studied using a mouse model known as experimental cerebral malaria (ECM). Although Plasmodium berghei ANKA (PbA)-induced ECM recapitulates some of the features of human CM, the disease pathology differs considerably. While human CM is characterized by sequestration of infected red blood cells (iRBCs) to the cerebral microvasculature, with minute inflammatory changes in the brain, murine ECM shows little or no intracerebral sequestration of iRBCs but a prominent proinflammatory cytokine response in the brain. Moreover, human postmortem reports revealed no intracerebral accumulation of CD8 + T cells, whereas intracerebral accumulation of CD8 + T cells is essential for the development of ECM (reviewed in detail by White et al. [5]). These differences need to be considered while translating murine studies to human malaria....