Malaria epidemics affect nonimmune populations in many highland and semi-arid areas of Africa. Effective prevention of these epidemics is challenging, particularly in the highlands where predictive accuracy of indicators is not sufficiently high to allow decisions involving expensive measures such as indoor residual spraying of insecticides. Advances in geographic information systems have proved useful in stratification of areas to guide selective targeting of interventions, including barrier application of insecticides in transmission foci to prevent spread of infection. Because rainfall is associated with epidemics in semi-arid areas, early warning methods based on seasonal climate predictions have been proposed. For most areas, response measures should focus on early recognition of anomalies and rapid mass drug administration. Vector control measures are useful if abnormal transmission is highly likely and if they can be selectively implemented at the early stages of an outbreak.