Plasmodium vivax is responsible for more than 100 million clinical cases yearly. Unlike P. falciparum, in which infected red blood cells cytoadhere via variant proteins, avoiding passage through the spleen, P.-vivax-infected reticulocytes seem not to cytoadhere. However, a variant subtelomeric multigene vir family has been identified in P. vivax. Thus, questions remain about how P. vivax circulates through the spleen and the role of Vir proteins. In this review, the importance of the vir multigene superfamily is reviewed in the light of the completion of the entire genome sequence of P. vivax and from data gathered from experimental infections in reticulocyte-prone non-lethal malaria parasites and natural P. vivax infections.