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Abstract: Protozoal infections exert significant health, community, and economic impact globally, primarily in tropical and subtropical regions. Due to the absence or inefficacy of vaccines for deadly protozoal illnesses, chemotherapy is a primary means for preventing such diseases. Growing drug resistance, rising cross-resistance, and a lack of new agents with novel modes of action all significantly reduce the effectiveness of current antiprotozoal treatments. Society seems to be ignorant of the extent and repercussions of drug resistance associated with anti-infective agents, even though it is a reality. Evidence suggests that reduced drug uptake, reshaped drug targets, genetic modifications resulting in loss of drug activity, and decreased drug export from parasites contribute to resistance development. Recently, there has been a significant gain in our understanding of drug resistance by isolating and characterizing genes and proteins associated with resistance. This fact has also paved the way for the discovery of potential new drugs. This review focuses on drug resistance in the most common vector and foodborne human-recovered parasites.