Most studies of the natural history of Plasmodium falciparum infection have been performed in areas of stable malaria transmission and the acquisition of immunity to malaria in individuals who live in such areas is well documented. For the past 10 years, we have monitored host-parasite relationships in an area characterized by unstable and seasonal malaria of low transmission intensity. The work was performed in the village Daraweesh located in north-eastern Sudan 16 km from Gedaref town. The climate of the region is characterized by well-defined wet and dry periods with a short rainy season followed by a long dry season. In some years the rains fail and there is little precipitation even during the wet season. Malaria cases are rare in the dry season and during droughts. In years with rains, falciparum malaria sweeps through Daraweesh during the wet season and 20-40% of the entire population suffer at least 1 attack of malaria. All age-groups are affected, but the risk of getting a clinical attack is about twice as high in the age-group from 5 to 20 years as in adults aged above 30 years. Serological data and evidence obtained by polymerase chain reaction indicate that only about half of new blood-stage infections cause clinical disease. Together these findings suggest that many new infections are controlled immunologically and that individuals aged over 30 years are more successful in controlling infections than are teenagers. Parasite strains collected in Daraweesh are genotypically diverse and it is likely that the outcome of new P. falciparum infections depends on the preparedness of the host immune system to mount an attack against polymorphic or variable antigens expressed by the infecting parasite.