Heme is cytotoxic to the plasmodium parasite, which converts it to an insoluble crystalline form called hemozoin (malaria pigment) in erythrocytes during replication. The increased serum levels of free heme cause tissue damage, activation of microvascular endothelial and glial cells, focal inflammation, activation of apoptotic pathways, and neuronal tissue damage. Several hypotheses have been proposed to explain how these causative factors exacerbate fatal malaria. However, none of them fully explain the detailed mechanisms leading to the high morbidity and mortality associated with malaria. We have previously reported that heme-induced brain microvascular endothelial cell (HBVEC) apoptosis is a major contributor to severe malaria pathogenesis. Here, we hypothesized that heme (at clinically relevant levels) induces inflammation and apoptosis in HBVEC, a process that is mediated by independent proinflammatory and proapoptotic signaling pathways. In this study, we determined the key signaling molecules associated with heme-mediated apoptosis in HBVEC in vitro using RT 2 profiler polymerase chain reaction array technology and confirmed results using immunostaining techniques. While several expressed genes in HBVEC were altered upon heme stimulation, we determined that the apoptotic effects of heme were mediated through p73 (tumor protein p73). The results provide an opportunity to target heme-mediated apoptosis therapeutically in malaria-infected individuals.