The Plasmodium spp. parasite was identified as the causative agent of malaria in 1880, and the mosquito was recognized as the vector in 1897. Despite subsequent efforts focusing on the epidemiology, cell biology, immunology, molecular biology, and clinical manifestations of malaria and the Plasmodium parasite, there is still no approved vaccine for the prevention of malaria. Physical barriers such as mosquito nets and screens, as well as chemical prevention methods like insecticides and mosquito repellents aimed at preventing the transmission of the disease, are not very effective. Furthermore, the resistance profile of the parasite to chemoprophylactic and chemotherapeutic agents is increasing. The beginning of the new millennium has seen a resurgence of interest in the disease by government and philanthropic organizations, yet we continue to face the complexities of the parasite, the host, and the vector.