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The ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations associated with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is associated with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ~1 h). Importantly, some ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivatives. Here, we describe recent progress made towards understanding ozonide antimalarial activity and discuss ozonide utility within the context of artemisinin resistance.