Malaria is an important cause of morbidity, but not everyone infected with the malaria parasite becomes seriously ill or dies. In areas of stable endemicity, repeated exposure to the parasite leads to the acquisition of specific immunity, which restricts serious problems to young children; malaria in older subjects causes a relatively mild febrile illness. However, even in people exposed to malaria for the first time, there is a range of possible outcomes, from death at one extreme to the occasional subject who appears resistant to infection at the other. In this case, any resistance is non-specific; it does not depend on prior exposure to malaria and may be either acquired or innate. Of course, the situation is not necessarily clear-cut and in any one individual several factors may interact, for instance when innate genetic factors exert their effect on the acquisition of specific immunity. Much of this chapter is concerned with specific acquired immunity to malaria; how it might work, what goes wrong with it and the possibilities for manipulation by vaccination. However, we begin with a brief outline of important innate and acquired factors that lead to non-specific immunity.