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No one knows exactly why resistance to malaria drugs always emerges first in this remote western province of Cambodia, nestled in the Cardamom Mountains. “The reasons are as much social as biological,” says malariologist Tom Peto, who is here in this dusty, unremarkable-looking town battling the latest threat to global malaria control: multiple drug–resistant (MDR) malaria.

Migrant workers such as this man in Pailin, Cambodia, near the border with Thailand, are at especially high risk of contracting malaria. Jeffrey Lau

PAILIN, CAMBODIA—Whatever the reason, this is where it starts. Resistance to chloroquine surfaced here in the 1950s before sweeping through the wider Mekong region and then into India and Africa, causing millions of deaths. Sulfadoxine-pyrimethamine went next, in the 1960s. Mefloquine failed in the 1970s.

Then in late 2008 and 2009 came reports that rocked the malaria world: Artemisinin, the so-called wonder drug that has sent malaria deaths plummeting across the globe over the past decade, was losing its effectiveness here. That sparked global alarm and prompted an ultimately futile emergency plan to contain resistance in Cambodia before the last, best drug was lost.

Now, Pailin is the epicenter of what some say is the greatest threat yet to malaria control: the deadliest malaria parasite, Plasmodium falciparum, has become resistant not only to artemisinin, but to a key partner drug, piperaquine, or PPQ, that is used in combination with artemisinin and is critical to its success. The emergence of this MDR parasite is raising the specter of untreatable malaria in the Mekong region and perhaps beyond.

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