Malaria remains a major disease of mankind, and resistance to existing 
therapeutics is rapidly emerging. Limited financial investment to develop new 
therapeutics requires the careful selection of well-defined targets from the 
causative parasite, Plasmodium falciparum. In these circumstances, protein 
crystallography can provide valuable structural detail to facilitate both the 
selection of suitable targets and the development of compounds to provide novel 
drug candidates. This review summarises the current involvement of 
crystallographic studies in anti-malarial drug development programmes. Protein 
crystallography is increasingly central to the exploitation of a number of 
potential Plasmodial targets. including the aspartic acid proteases 
(plasmepsins) and cysteine proteases (falcipains) involved in haem degradation 
within the parasite food vacuole. Lead compounds are being identified from 
collections previously synthesised against homologous human enzymes. Plasmodium 
have an unusual dependence on the glycolytic pathway relative to their human 
hosts, and this is reflected in subtle structural differences identified in the 
crystal structures of a number of parasite glycolytic enzymes including aldolase 
and lactate dehydrogenase. Other enzymes from a range of biosynthetic pathways 
have also been targeted in crystallographic studies. These include dihydrofolate 
reductase, the target of existing anti-folate therapeutics, and enoyl reductase 
from the fatty acid biosynthesis pathway which is already the target of 
effective bacteriocides. Crystal structures of these drug-enzyme complexes not 
only allow visualisation and improvement of inhibitor-protein contacts, but in 
the former case have also been used to probe the molecular basis of emerging 
anti-malarial drug resistance. Crystallography is similarly proving valuable as 
a tool to facilitate the development of inhibitors of purine salvage, isoprenoid 
synthesis and utilisation, and protein processing mechanisms.