Malaria continues as a major health threat throughout the tropical world and potential demand for antimalarials is higher than for any other medication yet the world faces a crisis-drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new drugs has all but stopped. This represents a particular threat to the U.S. Military. In a short time there may be parts of the world where no effective antimalarial drug is available. The recent emergence of multidrug resistant malaria parasites has intensified this problem. Recognizing this emerging crisis, it is necessary to identify new strategies for the identification and development of new antimalarials. The goal of this work is the development of a framework for antimalarial drug development into the 21st century. A new strategy for drug development is urgently needed. Current drugs are based on a small number of target molecules or lead compounds and in most cases the target of drug action is yet to be identified. Resistance is emerging rapidly and the mechanisms of resistance are poorly understood. The identification of new targets or new candidate drugs based on an understanding of the parasite biology are key elements in this new strategy. Clearly the development of a new antimalarial will require both basic and applied research working in concert with one another. The goal of this work is to use a molecular genetic approach both in the identification of new drug targets and in the investigation of mechanisms of drug resistance. During the preceding period, the research has focused on the two objectives, namely the analysis of critical genes in the Plasmodium falciparum for their role in drug resistance and as potential new drug targets using both the homologous P. falciparum system and the heterologous yeast system.