Malaria remains one of the biggest health problems in large parts of the world. In sub-Saharan Africa alone, it is currently estimated that there are more than 150 million clinical cases annually, and that about 2 million people die from the disease every year. The bulk of malaria-related morbidity and mortality in an endemic setting (malaria is regularly found) is concentrated in children below the age of five years, and the increasing resistance to infection and disease with age is conventionally thought to reflect a slow and gradual acquisition of protective immunity. Many recent and comprehensive reviews of malarial immunity exist; rather than attempting to add another, this review summarises some of the recent evidence on how protective immunity is acquired in humans and what precipitates clinical disease, specifically as it relates to populations living in areas where the disease is endemic. It is becoming increasingly clear that naturally acquired protective immunity depends largely on responses directed against highly variable parasite antigens. This implies that a successful blood-stage vaccine against this disease must be able to either induce protective responses against many of these variants, or artificially initiate protective immune responses that do not normally occur following natural exposure to the parasites. Such protective immune responses might either rely on a different immunological mechanism, or be directed against other antigens, other than those seen in naturally acquired protective immunity. It remains to be seen whether it will be possible to induce protective responses such as these by ‘artificially’ immunising humans.