The world faces the growing problem of multidrug-resistant Plasmodium falciparum, and chloroquine and primaquine-resistant Plasmodium vivax. Despite a seemingly large armamentarium of antimalarial drugs with various molecular targets, there are no regimens for the prevention or treatment of infection that are without some failures or some potential toxicity. Recommended chemoprophylactic regimens vary and controversy persists regarding their safety and efficacy. Furthermore, funding for malaria control and drug development has diminished. The wise use of available agents and the support of collaborative research efforts are necessary to address the problem of multidrug resistance and to develop novel approaches to malaria prevention and treatment. This review will focus on the recommended regimens for chemoprophylaxis of P. falciparum, and some of the newer agents and alternative strategies used for treatment.