The parasite Plasmodium falciparum is now resistant to most drugs currently used to treat malaria. Resistance to drugs, such as antifolates, arises from mutations in P. falciparum dihydrofolate reductase–thymidylate synthase (PfDHFR-TS) — a bifunctional protein that catalyzes sequential reactions in the thymidylate cycle. Inhibition of PfDHFR-TS prevents dTMP production and DNA synthesis, but how the resistance mechanisms operate at the structural level remains unclear. In the April 21 advanced online Nature Structural Biology Jirundon Yuvaniyama and colleagues from Mahidol University, Bangkok, Thailand, describe the crystal structure of PfDHFR-TS, which may explain some of the antifolate resistance mechanisms (Nature Structural Biology, DOI:10.1038/nsb921, April 21, 2003).