The epidemiology survey of Pfcrt and Pfmdr 1 mutant genes in malaria infection in Edo State was carried out between June 2005 and May 2006. Five hundred and sixty one (561) subjects with a history of fever, joint pains, and bitterness of the mouth were enlisted for this study. With regard to place of residence, 229 subjects were from Edo South, 177 from Edo Central and 155 from Edo North. Genotyping of resistance markers “Plasmodium falciparum Chloroquine Resistance Transporter” (Pfcrt K76T) and Plasmodium falciparum Multi-Drug resistance (Pfmdr1) was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). There was no statistical difference (P>0.05) in the prevalence of malaria infection among the three senatorial districts (90.8%, 94.2% and 96.1% respectively). The general prevalence of mutant Pfcrt K76T and Pfmdr 1 mutant genes in the state were 21.9% and 15.1% respectively. No statistical difference existed when the prevalence of these genes was compared within the senatorial districts (P>0.05). The treatment of malaria has reached a crisis point in the sub-Sahara regions. The present findings also revealed a relatively high prevalence of these resistance genes in Edo State, underlining the need for urgent policy intervention before the situation escalates beyond control.