The article reports the genome sequence of *Plasmodium falciparum* clone 3D7, the parasite responsible for the majority of malaria cases and deaths. The 23-megabase genome consists of 14 chromosomes, encoding about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. The genome contains genes involved in antigenic variation concentrated in subtelomeric regions, fewer enzymes and transporters compared to free-living eukaryotic microbes, and a large proportion of genes devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides a foundation for future studies and is being used to develop new drugs and vaccines against malaria. The article also discusses the sequencing strategy, genome structure and content, chromosome structure, proteome, evolution, metabolism, transport, DNA replication, repair, and recombination.The article reports the genome sequence of *Plasmodium falciparum* clone 3D7, the parasite responsible for the majority of malaria cases and deaths. The 23-megabase genome consists of 14 chromosomes, encoding about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. The genome contains genes involved in antigenic variation concentrated in subtelomeric regions, fewer enzymes and transporters compared to free-living eukaryotic microbes, and a large proportion of genes devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides a foundation for future studies and is being used to develop new drugs and vaccines against malaria. The article also discusses the sequencing strategy, genome structure and content, chromosome structure, proteome, evolution, metabolism, transport, DNA replication, repair, and recombination.