Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia1, 2. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated3, and it has a close phylogenetic relationship to Plasmodium vivax 4, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone5) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome4 and other sequenced Plasmodium genomes6, 7, 8. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs9, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.

For many pathogens the availability of genome sequence, permitting genome-dependent methods of research, can partially substitute for powerful forward genetic methods (genome-independent) that have advanced model organism research for decades. In 2002 the genome sequence of Plasmodium falciparum, the parasite causing the most severe type of human malaria, was completed, eliminating many of the barriers to performing state-of-the-art molecular biological research on malaria parasites. Although new, licensed therapies may not yet have resulted from genome-dependent experiments, they have produced a wealth of new observations about the basic biology of malaria parasites, and it is likely that these will eventually lead to new therapeutic approaches. This review will focus on the basic research discoveries that have depended, in part, on the availability of the Plasmodium genome sequences.

Malaria's moment has come, but success in control, let alone eradication, demands a renewed commitment to basic research. A Global Malaria Action Plan, announced at the UN Millennium Development Goals Malaria Summit in New York on 25 September, has the ambitious goals of both reducing the malaria burden and eradicating the disease entirely. Eradication any time soon might seem hopelessly optimistic, given the failure so far to make a serious dent in the number of malaria deaths. But much of the 274-page plan makes good sense. It calls for scaling up the use of existing tools, such as bednets, drugs and spraying, to near universal coverage, and then sustaining this effort for decades. True, this won't come cheaply. Funds for control have already grown from US$250 million annually in 2004 to an estimated US$1.1 billion this year; the plan calls for increasing that to $5 billion annually until at least 2020. Likewise, total spending on malaria-related research has risen from $265 million in 2003 to $422 million in 2007; the plan would see that figure double to between $750 million and $900 million annually until 2018. Whether donors will rise to the challenge is a big question, given current economic woes. Still, it is heartening that at the summit, donors from governments, industry and philanthropic organizations pledged US$3 billion. Striking the right balance between basic and applied research is also critical. For example, the sequencing in 2002 of the genome of Plasmodium falciparum, the main parasite that causes malaria, has stimulated the hunt for new drug and vaccine candidates. This week's issue of Nature sees the addition of two more parasite sequences: P. vivax, which is less deadly than P. falciparum, and P. knowlesi, which mainly infects monkeys (pages 751, 757 and 799). These new sequences show how much more there is to learn: more than half of P. falciparum's encoding genes still have no known function.

Four distinct Plasmodium species are known to regularly infect humans: Plasmodium falciparum, P. vivax, P. malariae and P. ovale. The genome sequence of P. falciparum, the cause of the most severe type of human malaria, was completed in 2002 at the same time as the mosquito vector, Anopheles gambiae. In this week's Nature, which focuses on the malaria parasite, two further malaria genome sequences are described. First that of P. vivax, which contributes significant numbers to malaria incidence in humans, though in contrast to P. falciparum, the resulting disease is usually not fatal. The genome of this rather neglected species is presented together with a comparative analysis with the genomes of other Plasmodium species. Second, we publish the genome sequence of Plasmodiumknowlesi. For long regarded as a monkey malaria parasite, it is increasingly becoming recognized as the fifth human-infecting Plasmodium species. In particular, it is prevalent in South East Asia where it is often misdiagnosed as another human malaria parasite P. malariae. As a model organism P. knowlesi stands out: not only is it a primate system, useful for work on vaccines, but it can be cultured in vitro and subjected to efficient transfection and gene knockouts. In a Review Article, Elizabeth Winzeler considers the progress made towards using the genome sequence to understand basic malaria parasite biology, and in particular the work on developing rational therapeutic approaches to combat P. falciparum infections.