Proliferation and differentiation inside erythrocytes are important steps in the life cycle of Plasmodium spp. To achieve these, the parasites export polypeptides to the surface of infected erythrocytes; for example, to import nutrients and to bind to other erythrocytes and the host microvasculature. Binding is mediated by the adhesive polypeptides Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), subtelomeric variant open reading frame (STEVOR) and P. falciparum erythrocyte membrane protein 1 (PfEMP1), which are encoded by multigene families to ensure antigenic variation and evasion of host immunity. These variant surface antigens are suggested to mediate the sequestration of infected erythrocytes in the microvasculature and block the blood flow when binding is excessive. In this Review, we discuss the multigene families of surface variant polypeptides and highlight their roles in causing severe malaria.