Malaria has prehistoric origin as a lethal human infectious disease. At about 10,000 years ago, malaria disease started having a major impact on human survival, coinciding with the start of civilization of agriculture in the Neolithic revolution. Malaria can be transmitted—with varying degrees of efficiency—by more than 100 species of Anopheles mosquitoes. Despite the progress of the last decades, the WHO report established that in 2018 there were 228 million cases of malaria worldwide and 405,000 global deaths. Until now, there is no effective vaccine available to prevent malaria, but there are many prescribed antimalarial medications to prevent the spreading of the disease. In high-burden countries, the most vulnerable populations at risk for malaria tend to be women and children and people living in poverty. Children are especially at risk, because they have not yet built up the partial immune protection that adults acquire from multiple, sustained infections. Also, pregnant women are at risk because of placental infection (30 million women living in Sub-Saharan Africa, with more than 200,000 newborn deaths each year, WHO 2016). Malaria and HIV (human immunodeficiency virus) co-infections occur in more than 3 million cases annually and result in 65,000 additional deaths. Malaria disease was endemic until 1945 throughout much of southern Europe. The Balkans, Italy, Greece and Portugal were particularly affected. Despite the substantial number of imported malaria cases in the last decade in European countries, autochthonous transmission has not been widely observed in Europe, probably as a result of early diagnosis and treatment, afforded by efficient healthcare systems. In December 2019, WHO published its world malaria 2019 report with the regional and global trends, The majority 93% of malaria cases in 2018 were in the African Region (213 million), followed by the South-East Asia Region (Indonesia, Laos, Malaysia, the Philippines, Singapore, Thailand, Vietnam, etc) with 3.4% of the cases and the Eastern Mediterranean Region (Egypt, Jordan, Syria, Labanon, Tunisia, Lebanon, etc) with 2.1%. Despite 50 years of research, the complexity of Plasmoidum falciparum confounded all attempts to eradicate the organism. This very complexity has pushed the boundaries of vaccine development to new heights, Novel vaccine such as RTS,S/AS01E are on the edge of licensure, but old techniques have resurged with the ability to deliver vialed, whole organism vaccines. This review contains some important facts on global malaria infections and the historial background for the development of therapeutic drugs and prevention measures that control the vector transmissions..