**Abstract**

*Plasmodium falciparum*, the most devastating human malaria parasite, confers higher morbidity and mortality. Although efforts have been made to develop an effective malaria vaccine, stage- and species-specific short-lived immunity crippled these efforts. Hence, antimalarial drug treatment becomes a mainstay for the treatment of malaria infection in the wake of the unavailability of an effective vaccine. Further, there has been a wide array of antimalarial drugs effective against various developmental stages of *P. falciparum* due to their different structures, modes of action, and pharmacodynamics as well as pharmacokinetics. The development of resistance against almost all frontline drugs by *P. falciparum* indicates the need for combination therapy (artemisinin-based combination therapy; ACT) to treat patients with *P. falciparum.* A higher pool of parasitemia under discontinuous *in vivo* artemisinin drug pressure in a developed humanized mouse allows the selection of artesunate resistant (ART-R) *P. falciparum*. Intravenously administered artesunate, using either single flash doses or a 2-day regimen, to the *P. falciparum*infected human blood chimeric NOD/SCID.IL-2Rγ−/<sup>−</sup> immunocompromised (NSG) mice, with progressive dose increments upon parasite recovery, was the strategy deployed to select resistant parasites. Parasite susceptibility to artemisinins and other antimalarial compounds was characterized *in vitro* and *in vivo*. *P. falciparum* has shown to evolve extreme artemisinin resistance as well as co-resistance to antimalarial drugs. Overall, the present information shall be very useful in devising newer therapeutic strategies to treat human malaria infection.

**Keywords:** artemisinin, artesunate resistance, co-resistance, *Plasmodium falciparum*, humanized mouse model
