Malaria is an ancient disease that continues to cause enormous human morbidity and mortality. The life cycle of the causative parasite involves multiple tissues in two distinct host organisms, mosquitoes and humans. However, all the clinical symptoms of malaria are a consequence of infection of human erythrocytes. An understanding of the basic mechanisms that govern parasite invasion, remodeling, growth, and reinvasion of erythrocytes and the complex events leading to tissue pathology may yield new diagnostics and treatments for malaria. This approach is revealing a more complete picture of the most serious syndrome associated with this infection-cerebral malaria. We focus on the most recent understanding of the molecular basis of infection, summarize our finding from an ongoing pediatric cerebral malaria autopsy study in Malawi, and integrate these insights to malarial pathology.