For 400 years, quinine has been the effective antimalarial. From a pulverized bark, which stopped cyclic fevers, to an easily isolated crystal alkaloid, which launched many pharmaceutical companies, tons of quinine are still purified for medicinal and beverage use. The quest for quinine synthesis pioneered early medicinal dyes, antibacterials, and other drugs. In a specialized Plasmodium lysosome for hemoglobin degradation, quinine binds heme, which inhibits heme crystallization to kill rapidly. Although quinine drug resistance was described 100 years ago, unlike chloroquinine or the antifolates that have been rendered ineffective by the spread of resistant mutants, quinine has only a few persistent, resistant parasites worldwide. The artemisinin drugs, superior to quinine for severe malaria, have greatly reduced the use of quinine as an antimalarial. Evidence for prolonged artemisinin parasite clearance times both renews the quest for rapidly parasiticidal drugs for severe malaria and possibly holds a place for quinine.