This chapter X-rayed antimalarial drug resistance (ADR) by plasmodium species with a particular focus on P. falciparum, which is the most deadly species of the malaria parasite responsible for over 90% of the global malaria burden domiciled in Sub-Saharan Africa. The introduction intently looked at malaria therapeutics across the decades and the development of drug resistance by the parasite. With the malaria parasite (P. falciparum) as the focal point, the mechanisms by which they develop resistance to antimalarial drugs was looked at, including factors affecting drug resistance development. Armed with this knowledge, the chapter also highlighted the therapeutic interventions taken against this hydra-headed monster together with their limitations and recent advances towards addressing those limitations or opening new frontiers for research exploration. Future perspectives that will provide research strategy and direction as possible tools for combating drug resistance development by the malaria parasite were also discussed.