Malaria remains a major public health problem worldwide. Despite many efforts to control or to eliminate the disease many malaria cases and deaths are still reported. The current measures to control malaria include quick diagnosis and treatment of malaria cases, vector control strategies, active research for malaria vaccine discovery and new drugs. Resistance of Plasmodium falciparum to the common and affordable antimalarial drugs as well as the resistance of the malaria vector to usual insecticides has been reported. An effective and affordable malaria vaccine would be the most important tool to control malaria. To date there is no licensed malaria vaccine. Traditional approaches toward malaria vaccine discovery have shown their limitations because of the limited number of proteins that were evaluated. The completion of the genome sequence of Plasmodium falciparum as well as the availability of the high throughput protein microarray immunoassay and other bioinformatic approaches offer the possibility to accelerate and to widen research on malaria vaccine candidates. The harnessing of the well-established model of the naturally acquired immunity (NAI) developed in people living in malaria endemic areas is an important way for the discovery of novel malaria vaccine candidates. Protein microarray is a high throughput technology, which allows the profiling of the humoral immune response to many proteins expressed at different stages of the Plasmodium life cycle in a single experiment. However, despite the hope generated by the sequencing of P. falciparum malaria genome no antigen identified by the protein microarray technology has yet been developed as a potential vaccine. On the other hand identification of structurally stable domains with limited or no polymorphism has led to the development of one candidate tested in phase 1a and 1b clinical trials.