Our understanding of the life cycle of the malaria parasites did not proceed in the logical order just outlined but more like a jigsaw in which the various pieces were painstakingly put into place and, like a jigsaw, often involved mistakes and false starts. The story begins with the discovery of the stages in the blood. Many textbooks merely state that 'in 1880 Laveran discovered the malaria parasite' words that do not give this discovery the credit it deserves. In order to understand the background of this discovery it is necessary to go back to the 1870s. The discoveries of Pasteur and Koch had precipitated a search for a bacterial cause for many diseases including malaria. By 1879 the miasma theory was going out of favour and the two theories vying for contention were whether the microorganisms responsible were transmitted (1) by air and inhalation or (2) by water and ingestion. The leading theory was that proposed by the Italian Corrado Tommasi-Crudeli and the German, Theodor Albrecht Edwin Klebs, an eminent microbiologist who had been the first person to see the bacteria responsible for typhoid and diphtheria. Tommasi-Crudeli and Klebs claimed that they had isolated from the waters of the Pontine Marshes, where malaria was prevalent, a bacterium, Bacillus malariae, which when isolated in culture and injected into rabbits caused febrile infections accompanied by enlarged spleens reminiscent of malaria . It was against this background that Charles Louis Alphonse Laveran, an unknown French army officer working in Algeria, challenged the perceived wisdom and began in his own words 'to follow the pigment'. Beginning with the known fact that the spleens of malaria patients contained pigment he began to look for pigment in the fresh unstained blood of patients and observed it first in leucocytes and then in or on red blood cells. Looking more carefully, he observed several different forms of erythrocytic organism including crescents, spherical motionless bodies with pigment, spherical moving bodies with pigment and bodies that extruded flagella-like structures all of which he thought were on the outside of the red cells. These observations are particularly interesting because Laveran not only used fresh blood but also a dry objective with a maximum magnification of ×400 diameters. He also suggested a course of events that began with clear spots that grew, acquired pigment and filled the corpuscle which then burst coinciding with the fevers associated with malaria. Laveran meticulously examined the blood of 200 patients and in 148 observed the crescentic bodies in all cases of malaria but never in those without malaria. He also noted that quinine removed these stages from the blood. Laveran quickly realised that he had found a parasitic protozoan which he called Oscillaria malariae. He presented his findings to the French Academy of Medical Sciences in December 1880  but failed to persuade any of the eminent microbiologists, zoologists or malariologists of the day that he was seeing anything other than disintegrating red blood cells. Nevertheless he persevered and by 1884 had convinced the leading Italian malariologists including Bignami, Golgi and Marchiafava that malaria was caused by a protozoan and not a bacterium . His biggest triumph came in the same year when he also convinced the more cynical microbiologists Louis Pasteur, Charles Edouard Chamberland and Pierre Paul Émile Roux. Robert Koch, one of the most influential microbiologists of his time, however, remained sceptical until 1887. Nevertheless in some quarters the miasma theory persisted and as late as 1895 the American R. C. Newton, a supporter of Tommasi-Crudeli, wrote that 'Aerial and aquatic transportation of malaria has been proved' . (This paper is worth reading in full because, although based on what we now know to be false premises, it contains a mass of interesting information about the prevention of malaria such as the use of screens or mosquito nets to exclude insects, closing doors at night and lighting fires out of doors). Laveran was awarded the Nobel Prize for Medicine in 1907 and his discoveries are described in some detail by the Sergent brothers  and Bruce-Chwatt  as well as in the various histories of malaria listed above.
By this time it had also become clear that the paroxsms characteristic of malaria coincided with the bursting of infected red blood cells and the release of the products of multiplication something that Laveran, who had also realised that in the case of malignant tertian malaria the brain was involved, had proposed . Thus by 1890 it was known that malaria was caused by a protozoan parasite that invaded and multiplied in red blood cells and, after a lot of confusion, that there were three species with specific periodicities and other characteristics responsible for benign tertian (Haemamoeba vivax), malignant tertian (Laverania malariae) and quartan (Haemamoeba malariae) malaria now respectively Plasmodium vivax, P. falciparum and P. malariae. The situation as it existed in 1900 is beautifully summarised by Grassi in his monograph, Studi di uno Zoologo Sulla Malaria and, although more details have since been added, this work remains as relevant today as it was 110 years ago. In 1918, John Stephens, working in West Africa, discovered a fourth species which resembled P. vivax which he described as P. ovale in 1922 .
One of the most important breakthroughs in malaria research was the development of techniques that enabled scientists to grow the erythrocytic stages of malaria parasites in continuous culture pioneered by William Trager and J.B. Jensen  thus freeing investigators from the need to use animals for chemotherapeutic and biochemical studies. The importance of this discovery cannot be overemphasised. For the first time, scientists had access to unlimited quantities of human malaria parasites, particularly P. falciparum, thus reducing their dependence on laboratory animals and blood taken from humans. The ease with which the erythrocytic stages could be grown in bulk made it possible not only to test the effects of drugs directly but also to isolate and purify parasite components in order to identify biochemical pathways and molecules of potential use in the development of vaccines and chemotherapy. The cultivation of sexual stages provided insights into the genetics of human malaria parasites and the development of drug resistance. The cultivation of liver stages, although more difficult to achieve, made it possible to develop and test drugs against these stages and provided vital information about the immune responses in the liver. Finally, the cultivation of sporogonic stages has enabled scientists to discover what happens to the parasite in its mosquito vector.
In natural malaria infections, SPZ are transmitted to humans by the bite of infective female Anopheles mosquitoes. The bite elicits an acute inflammatory reaction at the feeding site, resulting from the saliva of mosquitoes that contains pro-inflammatory  as well as anti-hemostatic  agents that facilitate the blood feeding process. The hypothesis of this analysis is that the local inflammatory reaction may not only benefit the feeding mosquito but also improve the chances of parasites successfully entering the blood stream and in turn, establishing a malaria infection in the mammalian host.
The impact of sickle cell trait on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Sickle cell trait causes a change in the haemoglobin molecule in the blood. Normally, red blood cells have a very flexible, biconcave shape that allows them to move through narrow capillaries; however, when the modified haemoglobin S molecules are exposed to low amounts of oxygen, or crowd together due to dehydration, they can stick together forming strands that cause the cell to distort into a curved sickle shape. In these strands, the molecule is not as effective in taking or releasing oxygen, and the cell is not flexible enough to circulate freely. In the early stages of malaria, the parasite can cause infected red cells to sickle, and so they are removed from circulation sooner. This reduces the frequency with which malaria parasites complete their life cycle in the cell. Individuals who are homozygous (with two copies of the abnormal haemoglobin beta allele) have sickle-cell anaemia, while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria without severe anaemia. Although the shorter life expectancy for those with the homozygous condition would tend to disfavour the trait's survival, the trait is preserved in malaria-prone regions because of the benefits provided by the heterozygous form.
In places where microscopy is unavailable, malaria is diagnosed with RDTs, rapid antigen tests that detect parasite proteins in a fingerstick blood sample. A variety of RDTs are commercially available, targeting the parasite proteins histidine rich protein 2 (HRP2, detects P. falciparum only), lactate dehydrogenase, or aldolase. The HRP2 test is widely used in Africa, where P. falciparum predominates. However, since HRP2 persists in the blood for up to five weeks after an infection is treated, an HRP2 test sometimes cannot distinguish whether someone currently has malaria or previously had it. Additionally, some P. falciparum parasites in the Amazon region lack the HRP2 gene, complicating detection. RDTs are fast and easily deployed to places without full diagnostic laboratories. However they give considerably less information than microscopy, and sometimes vary in quality from producer to producer and lot to lot.
Community participation and health education strategies promoting awareness of malaria and the importance of control measures have been successfully used to reduce the incidence of malaria in some areas of the developing world. Recognising the disease in the early stages can prevent it from becoming fatal. Education can also inform people to cover over areas of stagnant, still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is generally used in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas. Intermittent preventive therapy is another intervention that has been used successfully to control malaria in pregnant women and infants, and in preschool children where transmission is seasonal. 2b1af7f3a8