Abstract Malaria remains the most important human parasitic disease worldwide, causing over 170 million clinical cases per year, resulting in over a million die. Most of the treatments available have limited efficacy and side effects and the emergence of drug-resistant strains. Vaccines are being developed with varying degree of success. Host genetic factors also play an important role in susceptibility and clinical manifestations of infectious diseases. The mechanisms of natural protective immunity to malaria are not well understood, nor are the pathophysiological mechanisms of the disease. Most of the studies reported to date were based on case/control study of severe malaria and have tested genes based on biological functions or the distorted allelic distribution in the regions with high endemicity of malaria. Some of the genes, which will be identified through our approaches, may have no or little effect on the protection against sever malaria. Therefore, it is virtually impossible to identify these genes by studies conducted on severe malaria. The familial study that will be performed in this project enable us to test candidate regions, such as those homologous to the regions identified animal models as well as the whole genome search in a systematic way. This has a potential to identify new genes, which could not be detected through candidate gene approach.