The sickle cell hemoglobin variant (HbS) is known to confer resistance to the malaria parasite Plasmodium falciparum by various mechanisms that are not completely understood. Jen-Tsan Chi and colleagues investigated whether microRNAs (miRNAs) are involved in HbS-mediated malaria resistance and now report a novel miRNA-driven mechanism that contributes to malaria resistance in erythrocytes carrying the HbS variant (Cell Host Microbe 12, 187–199, 2012 ). The authors confirmed the presence of intact human miRNAs in the parasites and found enrichment of miR-451, miR-223 and miR-19b. They further showed that the miRNAs are transported into the parasite. The miRNAs are sufficient to confer resistance to wild-type HbAA red blood cells, and inhibition of miR-451 and miR-223 led to increased parasite growth in HbSS and HbAS red blood cells. P. falciparum does not encode Dicer/Ago orthologs, so it was not clear how the human miRNAs affect parasite growth. Unexpectedly, the authors found that the human miRNAs are covalently bound to Plasmodium mRNAs, which appears to inhibit translation. The results suggest that ectopic introduction of miR-223 or miR-451 may be a potential therapeutic strategy for malaria.