Recent work on the inheritance of susceptibility to malaria suggests that, over what may have been a relatively short evolutionary period, a remarkably diverse series of gene families have been modified in response to the selective drive of this single infection. The phenotype consequences are not confined to the red cell, but involve the immune system, cytokines and many other systems. It seems likely that the mechanisms of variation in genetic susceptibility to other infective agents will reflect at least a similar degree of complexity and, if the selective pressures have been present for longer periods of our evolutionary history, may be even more diverse. This may have important implications for work directed at trying to define susceptibility loci for current infectious and non-infectious diseases.