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In Africa, current antimalarial strategies rest on the use of the artemisinin combination therapies (ACTs). However, resistance to artemisinin has emerged in South East Asia, and experience indicates that this resistance would eventually reach Africa, a scenario that would be associated with increased malaria morbidity and mortality. Thus, more than ever, new drugs are urgently needed. One of the strategies to discover new drugs is to reposition or repurpose existing drugs, thus reducing the cost and time of drug development. For instance, some anticancer drugs (anticancers) such as methotrexate are potent against malaria. However, anticancers are commonly perceived to be too toxic, thus not suitable for malaria treatment. In this chapter, we examine (1) how the toxicity of anticancers is just a matter of dose or “only dose makes the poison,” as coined in Paracelsus’ Law; (2) and the potential of the anticancer methotrexate to treat malaria, thus demonstrating that the opportunity exists to discover new antimalarials using the anticancer pharmacopoeia.

The emergence and spread of resistance remain a burgeoning problem in the control and the management of malaria. Effort has been dedicated in discovering and developing new drugs; however, these efforts are hampered by the rapid selection of resistance. For instance, there is no single antimalarial in clinical use against which the parasite has not yet developed resistance. To counterbalance this rapid development of resistance, not only should new drugs be developed, but the mechanisms of resistance to existing drugs need to be fully understood. Indeed, understanding these mechanisms could lead to identifying simple ways, by the use of single markers, to map and monitor the emergence and spread of drug resistance. In addition, such studies could also contribute to clarifying the mode of action drug, which eventually could lead to the discovery of new targets and thus new drugs. In this chapter, we have reviewed our current knowledge and presented existing challenges and gaps, on the mechanisms of resistance to most clinically important antimalarials.