Treatment failure in the treatment of parasitic infections is largely attributed to resistance to treatment regimen. The resistance mechanisms discussed include decrease in medication uptake, the export of medicines from the parasite by P-glycoproteins and other traffic ATPases, and the putative involvement of the P-glycoprotein expressed by the Plasmodium falciparum pfmdr1 gene in chloroquine resistance. Resistance to several antimalarials and formation of multidrug resistance parasites have been linked to polymorphism, amplification, and variations in mRNA expression level of the Pfmdr1 gene. Designed as an analog of folic acid for cancer treatment, pyrimethamine is a 2,4-diaminopyrimidine structurally resembling proguanil and suspected to have antimalarial effects. Modern technology has given more insight into the reason behind some conventional resistance observed in drugs universally used for a global epidemic like malaria. For instance, a major driver of artemisinin resistance in P. falciparum has been linked to point mutation in the propeller region of K13 protein and higher resistance to artemisinin has been linked with nonsynonymous polymorphism at Y493H, R539T, and I543T. Again, C580Y is found in the kelch repeat region of K13 propeller domain, and M476I and D56V mutations were confirmed to have raised Tanzania’s artemisinin resistance.