Drug resistant malaria is mostly due to Plasmodium falciparum, a species highly prevalent in tropical Africa, Amazon and Southeast Asia. P. falciparum is responsible for severe involvement of fever or anaemia prompting more than a million deaths per year. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality in some human populations from endemic regions. Rationale for chemoprophylaxis is becoming week as multiple drug resistance against well tolerated drugs develops. Plasmodium falciparum drug resistant malaria originate from chromosomal mutations. Analysis using molecular, genetic and biochemical approaches has shown that Epidemiological studies have established that the frequency of chloroquine resistant mutants varies among parasites isolates populations while resistance to antifolinics is highly prevalent in most malarial endemic countries. An established and strong drug pressure and a low antiparasitic immunity probably explains the multidrug-resistance encountered in forests of Southeast Asia and South America. In Africa, frequent genetic recombinations in Plasmodium originate from a high level of malaria transmission, and falciparum chloroquine-resistant prevalence seems to stabilise at an equal level as chloroquine-sensitive malaria. Nevertheless, resistance levels may differs according to places and time. In vivo and in vitro tests are insufficient to give an accurate map of resistance. Biochemical tools at a low cost are urgently needed for a prospective monitoring of resistance.