Introduction: Malaria is a public health problem for approximately 2.4 billion people, 40% of the world’s population, particularly in the tropical and subtropical countries. Countries in Asia, and Latin America, the islands of the South, West, and central Pacific Ocean are all affected. DRUG RESISTANCE is the greatest challenge in combating against malaria. DRUG RESISTANCE in malaria is now widespread and increasingly has sophisticated the treatment in many parts of the world. This review study was conducted to determine the present situation of malaria DRUG RESISTANCE.Chloriquine, the most valuable antimalaria, has been the DRUG of choice for treatment of malaria all over the country almost for half a century. It is well absorbed, well tolerated, and inexpensive. However, the first report of chloroquine-resistant flaciparum malaria was published by Edrissian two decades ago. Consequently, mosquitoes of the Anopheles species spread the DRUG resistant parasite strians throughout the malarious areas of Iran. As a result, both prevalence and intensification of RESISTANCE has increased. Recent study has located several mutated genes responsible for plasmodium falciparum RESISTANCE to chloroquine and sulfadoxine/pyrimethamine combination. Application of genetic information for early detection of RESISTANCE foci and further monitoring of DRUG resistant malaria is a useful epidemiological tool in comparison with traditional methods. There is much to be done in the research of malaria and its treatment.Conclusion: Education on the prevention of malaria is greatly needed. Treatment of malaria with a single DRUG should no longer be regarded as ethical. Combination of two antimalarial with independednt mode of action should replace the conventional treatment. Although, recently combination of chloroquine and fansidar has been introduced as the first line treatment in falciparum malaria, nevertheless experiences in other countries reveal that such a combination is not suitable. It is highly suggested that the present first line DRUG should switch to the newly formulated antimalarials, i.e. artesunate, a derivative of artemisinine, not only is able to diminish the problem, but also due to its brilliant therapeutic efficacy, resolves the patient’s symptoms rapidly and prevents treatment failures as well. Furthermore, gametocyte rate will decrease too.