Resistance of Plasmodium falciparum to artemisinin (ART) combination therapies is increasing in Southeast Asia, but the mechanisms of resistance have been unclear. Now, using a combination of in vitro, in vivo, genomic and epidemiological approaches, Ariey et al. show that mutations in the 'propeller domains' of the kelch protein K13 are a key determinant of resistance. These proteins contain multiple repetitive amino acid sequences and are thought to be involved in several protein–protein interactions. K13-propeller mutations were prevalent in clinical parasite isolates from regions where ART resistance is widespread but were rare or absent in regions where resistance is uncommon. Clinical ART resistance is defined by prolonged parasite clearance rates, and the K13-propeller mutations were also found to strongly correlate with the presence of slow-clearing parasites. The identification of these mutations is a crucial advance for efforts that aim to monitor and contain the spread of ART resistance.