Recent epidemiological evidence has given increasing support to Haldane's 1949 hypothesis that heterozygotes for such genetic disorders as thalassaemia might be protected against malaria, hence explaining the high gene frequencies for such disorders in endemic areas. As discussed here by Yongyuth Yuthavong and Prapon Wilairat, the possible cellular mechanisms, although still unclear, are emerging from in vitro studies which increasingly point to the importance of immune clearance mechanisms in some cases (such as alpha-thalassaemia and haemoglobin E). In other situations, decreased survival of the intra-erythrocytic parasite or decreased parasite invasion of the variant red blood cells may explain the protective effect. Whatever the cellular mechanisms are, the ultimate decisive factor is the relative fitness of the infected variant host, which may not be simply extrapolated from the cellular studies.