Current first-line artemisinin antimalarials (ARTs) are threatened by the emergence of resistant Plasmodium falciparum. ART resistance has recently been linked to mutations in the K13 propeller protein. Our characterization of field strains (Pailin, Cambodia) shows that decreased sensitivity of ART resistant parasites is evident in the initial (early ring) stage of intraerythrocytic development, making it critical to understand the action of ARTs at this stage. We show that a specific hemoglobinase inhibitor (E64d) strongly antagonizes ART action at ring stage of the 3D7 strain, indicating a major role of heme in ART activation. The surprising implication that hemoglobin digestion is active in early rings is supported by pulldown-based identification of active hemoglobinases (falcipains) at this stage. We show that genetic down-modulation of the expression of the two main cysteine protease hemoglobinases, falcipains 2 and 3, renders early ring stage 3D7 parasites resistant to ARTs. This shows that changes in the rate of ART activation could mediate high levels of ART resistance. Our kinetic analysis of the K13 wildtype and mutant isolates reveals that exposure to short pulses of ARTs induces growth retardation in both sensitive and resistant parasites. Following this growth retardation, resistant strains survive, while sensitive parasites succumb. The data suggest that ARTs are activated, and cause cellular damage, in both strains, but resistant parasites are better able to withstand the damage. Since arrest in growth often reflects the cellular stress response, we postulated that ART resistance is caused by an up-regulated parasite cellular defense mechanism. Consistent with this, we demonstrate that proteasome inhibitors effectively synergize ART activity against both sensitive and resistance strains, with particularly strong synergism evident during the most resistant stage of the resistant strains. This suggests that the parasite proteasome system could be targeted to enhance drug action, offering a way to overcome ART-resistant malaria.