Malaria is endemic in Mayotte, with the potential to become epidemic. A gradual decline in incidence has been observed since 2001. Since April 2002, the treatment recommendations issued by the Department of Health and Social Affairs have been based on the first-line combination of chloroquine and sulfadoxine-pyrimethamine (Fansidar®). A review of studies conducted in Mayotte on drug resistance was carried out, along with a literature review. All currently available information on drug resistance in Mayotte indicates that, while current patient management remains effective, urgent consideration must be given to the potential and now anticipated emergence of resistance to first-line treatment. For several years, the WHO has recommended that countries with documented evidence of drug resistance adopt a sustainable strategy based on artemether-based combinations. The recent lifting in 2007 of some of the regulatory restrictions that had been an obstacle to the use of Riamet® (artemether/lumefantrine combination) in France should make it possible to implement robust and sustainable therapeutic strategies for the first-line treatment of uncomplicated malaria in Mayotte.