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Infectious diseases have been evolving and re-evolving over the ages and causing immense misery to humans. Among them, some have been prevented and eradicated, but few are still threatening the modern era since their origin. The majority of these infectious diseases are poverty-driven, hence highly prevalent in the lower-income and mid-income countries of Africa and Asia. The world’s deadliest infections, including Tuberculosis, Malaria and HIV/AIDS, have been considered as the “Big Three” infectious diseases (BTIDs). With leading infections and deaths every year, the BTIDs have been recognized as the world’s greatest pandemics. In light of these alarming situations, this review has been aimed to provide a comprehensive overview of the current status of chemotherapeutics, associated challenges and future perspectives of BTIDs.