Plasmodium falciparum malaria continues to impose a devastating burden on children in Sub-Saharan Africa. The pathogenesis of the most severe and life-threatening manifestations of the disease such as cerebral malaria and severe malarial anemia is complex and not well understood. Hallmarks of severe malaria include parasite sequestration and cytoadherence within the vasculature, processes that are mediated by P. falciparum variant surface antigens (VSAs) displayed on the surface of infected erythrocytes. The PfEMP1s are the most well characterized VSA family, and specific subtypes have been linked to severe malaria. The significance of the RIFIN and STEVOR VSA families in the pathogenesis of clinical disease has not been investigated. There is promising in vitro evidence implicating specific RIFIN and STEVOR antigens in vascular occlusion and suppression of the host immune system. However, the immense within-strain and between-strain genetic diversity of these families has complicated efforts to study their expression and roles in clinical infections. There are no studies connecting RIFINs or STEVORs to severe malarial disease in a clinical context. This dissertation aimed to untangle the web of RIFIN and STEVOR genetic diversity and illuminate subgroups that are specific to severe malaria syndromes. In Chapter III, I used alignment-free comparative genomics to robustly determine the genetic diversity among the RIFIN and STEVOR proteins and identify uniquely conserved “strain-transcendent” sequences. In Chapter IV, I used reference-free transcriptome assembly to comprehensively profile rif and stevor gene expression from ex vivo snapshots of clinical malaria infections among children in Mali and Malawi, revealing that immune system targeting subgroups were associated with severe malaria syndromes. Together, these studies build a strong foundation for further RIFIN and STEVOR research and provide compelling translational support for their consideration as key Plasmodium falciparum virulence factors. Importantly, my findings lay the groundwork for potential vaccines or adjunctive therapies to prevent, mitigate, or reverse severe malaria.