Clones of Plasmodium alter their antigenic profile or invasion phenotype when presented with specific challenges. Two examples are reviewed which may represent different genetic mechanisms of adaptation to selection pressures. In one series of experiments, rhesus monkeys were vaccinated with a 143,000/140,000 Mr P. knowlesi merozoite surface protein and then infected with a parasite clone expressing this protein. Primary parasitemia was controlled, but subsequent waves of parasitemia developed from populations of parasites harboring mutations in the 143,000/140,000 Mr gene. Mutations in this gene may be occurring at a continual low rate in the population (as with any normal gene) and particular mutations may have been selected in the vaccinated monkeys. In other experiments, P. falciparum parasite lines were selected from a clone (Dd2) that initially exhibited low rates of invasion into erythrocytes made sialic-acid deficient by neuraminidase treatment. After several growth cycles in neuraminidase-treated erythrocytes, a switch was observed and parasite lines were recovered that invaded neuraminidase-treated and normal erythrocytes at the same rate. The switch mechanism in invasion may represent another aspect of genetic variation, i.e. a programmed response in which certain genes are activated or rearranged. Vaccine trials in the future should include studies on the selection of mutations in the target antigen. Where switching mechanisms exist, knowledge of the genetic mechanisms that produce these adaptive responses will advance analysis of prospective vaccine candidates and contribute to our understanding of parasite biology.