This chapter discusses the advances in the chemotherapy of malaria. The search for the ideal antimalarial drug continues. Such a drug will combine the virtues of causal prophylaxis, suppression, rapid and complete curative action, and sporontocidal activity, together with no liability to produce resistance; it should have low toxicity, prolonged action, palatability, and low cost. This euphoric compound is unlikely to be forthcoming; nevertheless, new drugs are needed, particularly a good, safe anti-relapse drug to replace primaquine in the treatment of P. vivax and P. malariae infections, and a potent and safe blood schizontocide that will maintain its effect for 3–6 months after a single dose. The need for new drugs of protracted action is urgent especially when the aim of global eradication of malaria is to be pursued. The chapter reviews that most of the present antimalarials were discovered by empirical methods and are likely to continue so when the problem of therapy is so urgent, and the large-scale screening procedures are therefore of immense value. Structural refinements of existing drugs seem to hold little hope in solving the problem of drug-refractory malaria because most of the present drugs act by inhibition of nucleic acid function, albeit at different loci. The chapter concludes that malaria remains the major threat to life and one of the most serious public health problems in the underdeveloped nations. The main predisposing conditions for its emergence seem to be the influx of people, with low levels of immunity, into endemic areas, in presence of resistant mutant parasites, and free availability of antimalarial drugs.