Several FDA-approved antimalarial agents, including Malarone (atovaquone-proguanil), doxycycline, and mefloquine, are commonly recommended for preventing malaria in travelers going to malaria-endemic areas using a daily or weekly regimen. Recently, a safety evaluation of mefloquine and doxycycline versus Malarone participants demonstrated that those receiving mefloquine were more likely to discontinue their medication due to adverse effects compared to Malarone and doxycycline users. Although Malarone showed a better safety profile than mefloquine, the absolute risk of malaria during short-term travel appears low with all three agents. Adherence to malaria prophylaxis regimens needs improvement. Evidence from clinical and pharmacokinetics-pharmacodynamics (PK/PD) studies have confirmed that a shortened oral Malarone regimen may convey full protection to the gold-standard dosage regimen. There is another relevant aspect of Malarone PK/PD to consider, namely the very long blood schizonticidal effect which makes this combination attractive for consideration as the first line malaria prophylaxis. So far, there is no perfect option among available antimalarial regimens for long-term travelers and expatriates. Most prophylactic regimens provide about 75% to 95% protection, even if taken correctly, and no prophylactic regimen is 100% effective. To optimize the current regimens, the long-term prophylactic agents with monthly dosage as well as a yearly implantation design are being developed at the Walter Reed Army Institute of Research (WRAIR). In this topical review, we will explore the advantages of our long-term prophylaxis approach in comparison with current drug regimens. We will also examine the evidence behind current indications for the use of Malarone and will summarize the current body of literature surrounding its safety and efficacy. Additionally, this review demonstrates that Malarone may offer a statistically significant prevention benefit with a much longer and safer prophylactic efficacy.