Resistance to antimalarial drugs is a great threat to malaria elimination efforts and adds resurgency of malaria incidences and deaths. Rapid and indiscriminate use of drugs in the treatment of malarial infections has led to the emergence and spread of resistant strains. With condensed efforts for monitoring drugs resistance in clinical setup integrated by in vitro drug susceptibility assays and analysis of resistance markers can help in malaria eradication policy. In this chapter we discussed the demographical distribution of malaria throughout the world along with its clinical manifestations. We have also emphasized the mechanism of action underlying activity of FDA approved antimalarial drugs and also described effect of wide spectrum usage of antimalarials and combinational therapy against the deadly disease. Various factors leading to emergence of resistance including the mutation rate of the parasite for their bio-adaptation, the overall parasite load, strength of drug selection and treatment compliance. We summarize the chapter stating the number of probabilities which defines the future of antimalarial drug resistance and cumulative approaches to combat it. © Springer Nature Singapore Pte Ltd. 2019.