Significance The mitochondrial electron transport chain (ETC) of Plasmodium falciparum malaria parasites contains targets for antimalarial drug development including cytochrome B (PfCytB) and NADH dehydrogenase 2 (PfNDH2). Atovaquone (ATQ), a widely used antimalarial drug, is a hydroxynaphthoquinone inhibitor of PfCytB; substituted quinolone compounds (CK-2-68 and RYL-552) have also been developed as putative inhibitors of PfNDH2. Unexpectedly, our experiments yielded mutations of PfCytB, not PfNDH2, in parasites selected with these quinolones. ATQ selections yielded different PfCytB mutants that showed little change or slightly increased sensitivity to CK-2-68 or RYL-552. Differential patterns of drug response in various PfCytB mutants suggest that combinations of ETC inhibitors may help counter drug-resistant malaria.