Malaria is amongst the most common parasitic infections in the world. In Africa it causes one in every five childhood deaths, with one child dying of malaria every 30 seconds. People living in malaria endemic areas appear to have protective immune mechanisms, which may be naturally occurring or acquired from exposure to the malaria parasite. These protective factors play an important role in reducing morbidity and mortality from malaria. This review is aimed at exploring and explaining the mechanisms for a selection of the main protective factors to malaria in man. Using an exten- sive literature review of prominent articles, this paper identifies and summarizes these mechanisms which may be ac- quired or genetic. The challenge for the future will be to translate these notions into the development of interventions for the prevention and treatment of malaria.