Introduction: Malaria is a highly contagious disease. According to W.H.O., its cases are expected to increase due to climate changes. Despite eradication efforts, malaria still remains one of the most significant causes of morbidity and mortality in tropical and subtropical regions. Many different antimalarial regimens are used; however resistance is emerging to many of them. Purpose: This critical review was conducted, in order to respond to the following questions. A) Which antimalarial regimen is the most effective? B) Which regimen is the safest for travelers in endemic regions? C) Which regimen is best tolerated? Methodology: The literature research was conducted through the Internet. The Medline and Cinahl databases were used, as well as the search engines google, altavista and lycos. The research included clinical trial articles. The studies were selected based on the aforementioned research questions and the chronological time limits. Results: Atovaquone/proguanil, tafenoquine, primaquine were the most effective regimens. Tafenoquine, as well as, primaquine were related to hemolytic incidents in individuals with G6PD deficiency, gastrointestinal disorders, backache and flu-like syndrome. Doxycycline and mefloquine were related to gastrointestinal and neurological disorders. Those were the less tolerated regimens. Conclusions: Atovaquone/proguanil, tafenoquine, primaquine were the most effective regimens. As far as safety is concerned, tafenoquine and primaquine should not be prescribed to individuals with G6PD deficiency. All the regimens were considered well tolerated, while most withdrawals due to adverse effects, took place in the doxycycline and mefloquine trials.