Malaria has remained the leading cause of death in children under five years of age and pregnant women in sub-Saharan Africa and other endemic countries. The discoveries of Antimalarial drug especially the quinolones has led to the hope that malaria might be completely eradicated from the world. However, lack of proper understanding of the mechanisms of antimalarial drug action and resistance to major antimalarials currently in clinical use has doused our hope for malaria eradication in a near future. Here, the major antimalarials in clinical use, their modes of action and resistance profiles were reviewed. While drugs such as chloroquine were banned for reasons associated with resistance and safety in some countries like Nigeria, a proper understanding of their modes of actions in the malarial parasite could pave ways for discoveries and development of novel antimalarials with similar properties and targets. Other drugs such as the antifolates are still in use as Intermittent Preventive Treatments in Pregnancies (IPTPs) and Infants (IPTIs) respectively. Resistance to these drugs is driven by mutations of the drug target (DHFR and DHPS). Although Artemisinin combination therapies (ACTs) are widely in use in many malaria endemic areas, resisistance to these combination regimens defined as delayed parasite clearance were since reported. Four credible single nucleotide polymorphisms (SNPs); N86Y, N1042D, S1034C, and D1246Y were detected in the Plasmodium falciparum Multidrug Resistance Transporter gene-1 (PfMDR-1 gene) and implicated for artemisinin resistance while K76T mutation in the transmembran domain of malarial parasites is associated with resistance to quinolone antimalarials.