AbstractThe morbidity and mortality associated with malaria have spurred efforts to find novel antimalarial agents with improved potency and selectivity. Leads for agents continue to be obtained from natural sources (plants and microorganisms) and chemical syntheses. Screening of commercial or specialized databases have also yielded promising leads. The structural diversity of compounds with good (micromolar and lower) activity point to the considerable tolerance for different structural elements in the “antimalarial pharmacophore.” It may also be a reflection of the varied targets present in the plasmodia. The challenge in malaria chemotherapy is to find safe and selective agents whose potencies will not be compromised by plasmodial resistance. Modification of potential leads should also aim at improving “drug‐like” character, viz. to ensure acceptable oral bioavailability. A review of the literature shows that there is a growing trend towards the development of target‐specific antimalarial agents (for example, agents inhibiting plasmodial farnesyl transferase, cyclin dependent kinases, proteases, choline transport). An increasing number of reports focus on the development of chemosensitizers, agents that are capable of reversing plasmodial resistance. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 4, 456–487, 2003