In recent years infection with chloroquine-resistant Plasmodium falciparum has been combatted with two long-acting antimalarials, pyrimethamine and sulfadoxine, in the combination known as Fansidar that exerts a strong, synergistic action on the asexual stages of the parasite. This second-line regimen, however, is failing increasingly because of the selection of resistant clones in endemic areas, and effective, safe, alternative drugs or drug combinations that are also affordable are urgently needed. Antimalarial drugs with shorter half-lives than those of pyrimethamine or sulfadoxine are likely to be slower to select resistant parasites. In the experiments reported here, the baseline in-vivo responses of rodent malarial parasites to chlorproguanil and proguanil and their active metabolites, chlorcycloguanil and cycloguanil, as well as those to dapsone and artesunate, were explored. In general, the most sensitive parasite to all of these compounds was P. chabaudi. When the drugs were used, individually, to select resistance via the '2%-relapse technique', relatively stable resistance to each was obtained in P. chabaudi as well as in P. berghei and P. yoelii ssp. NS, the last of these being also highly resistant to chloroquine. Of most concern was the rapidity and high level of resistance developed by P. chabaudi to artesunate. The experiments also validated the use of chlorcycloguanil or cycloguanil as surrogates for chlorproguanil or proguanil. Further studies to investigate the possible value of administering chlorproguanil-dapsone, with or without artesunate, are under way and will be reported separately.