Mefloquine resistance in Plasmodium falciparum, the most dangerous of the four pathogenic malaria parasites of humans, is established in several endemic regions of the world. After a promising start, resistance has developed to disturbing extents in some areas, whereas in many regions it remains an effective drug. In this article, Frank Mockenhaupt reviews the factors that are likely to influence the development of mefloquine resistance, its possible mechanism and its geographical spread.