Malaria is an infectious disease that is widespread in tropical and subtropical regions. The malaria parasite is able to skip the host immunity and thus maintains not only persistent but also repeated infections. There are a number of multigene families in Plasmodium that code for the variant antigens and are targets for protective immunity. In this article, we summarize the virulence genes of P. falciparum (var genes) and P. vivax (vir genes) which play key roles in disease pathogenesis by evading elimination by the host immune system. These genes occurring within the parasite population are mostly present in the subtelomeric regions of the chromosome.