Most malaria is transmitted by the bite of an infective female Anopheles sp. mosquito. Most species feed at night; some important vectors also bite at dusk or in the early morning.

Malaria infection begins when an infective female mosquito injects Plasmodium sp. sporozoites into the bloodstream while feeding. The sporozoites pass almost immediately into the cells of the liver parenchyma, where they undergo asexual reproduction (exo-erythrocytic schizogony) and mature into schizonts. In 6 to 14 days, these schizonts mature and rupture, releasing merozoites into the bloodstream. Merozoites subsequently invade red blood cells and then undergo a second phase of asexual reproduction (erythrocytic schizogony). Once the erythrocytic schizonts mature, the infected red blood cells rupture, releasing more merozoites into the bloodstream, and beginning another cycle of asexual development and multiplication. Clinical symptoms occur with the rupture of erythrocytic schizonts, usually after several cycles of erythrocytic schizogony. The classical clinical presentation of periodic fever and shaking chills occurs when the cycles of erythrocytic schizogony are synchronized.

Some merozoites develop into sexual forms called gametocytes. Male and female gametocytes circulate in the blood without causing symptoms, and can then be ingested by a mosquito during a subsequent blood meal. Sexual reproduction occurs within the mosquito midgut, where male and female gametes unite to form an ookinete; the ookinete then penetrates the midgut wall and forms an oocyst. After maturation for days to weeks, the oocyst ruptures, releasing sporozoites, which migrate through the coelomic cavity to the salivary glands. The life cycle starts again when the infective mosquito bites another human.

The period between an infective bite and detection of the parasite in a thick blood smear is the “prepatent period,” which is typically 6–12 days for P. falciparum; 8–12 days for P. vivax and P. ovale; and 12–16 days for P. malariae. The period between the infective bite and the appearance of clinical symptoms is called the incubation period. Delayed primary attacks by some P. vivax strains may occur 6–12 months after exposure. Gametocytes usually appear in the bloodstream within 3 days of overt parasitemia with P. vivax and P. ovale, and after about 10 days with P. falciparum. Unlike P. vivax and P. ovale, relapses do not occur with falciparum or malariae malaria. Reappearance of P. falciparum (recrudescence) occurs due to inadequate treatment or infection with drug-resistant strains. With P. malariae, low levels of erythrocytic parasites may persist for many years, to be activated at some future time to a level that may result again in clinical illness.

Induced malaria refers to infection that is passed directly from one individual to another through contaminated blood or blood products, injection equipment, or organ transplant. Congenital malaria refers to infection passed from mother to infant in utero. Pregnant women in endemic areas, especially primi- and secundigravidae, are at increased risk of infection with P. falciparum and vivax malaria due to partial loss of immunity during pregnancy. In areas of intense transmission, P. falciparum may infect the placenta and contribute to low birth-weight as well as maternal anemia. In low transmission areas, pregnant women are at high risk of severe falciparum malaria, abortion and premature delivery. Vivax malaria in pregnancy in these areas has been associated with maternal anemia and low birthweight.