Most clinical manifestations of malaria are associated with the iRBC cycle. Not coincidentally then, nearly all known antimalarial drugs act against the iRBC. Understanding unique parasite biochemistry within the iRBC is essential since it is intricately linked to the molecular mechanisms of drug action and drug resistance for virtually all known antimalarial drugs. The past 10 years has shown that as these mechanisms are increasingly defined in molecular detail, this guides the rapid development of additional inexpensive antimalarials active against chloroquine (CQ) resistant (CQR) P. falciparum. Promising advances with partially protective vaccines notwithstanding, new antimalarial drugs will be direly needed for at least the next two decades, and probably longer. The above is just a glimpse at a very complex host-parasite biology that varies for different species and that protects multiple parasite stages from effective immune-system intervention in multiple ways. Childhood versus adult versus pregnancy-associated malarias differ, and common co-infections involving malarial parasites and other microbes pose additional therapeutic challenges. As a consequence, multiple vaccines will most likely be needed to eradicate malaria. Thus, it is imperative that equal emphasis be placed on inexpensive drug development and other approaches for controlling malaria.