Drugs that are active against gametocytes, the stages of the malaria parasite responsible for transmission, are recognized as key tools required for the global elimination of malaria. As the majority of drugs currently used to treat clinical malaria target asexual intra-erythrocytic parasites most have limited inhibitory effects on gametocytes. Only one drug, primaquine (PQ), is currently clinically available for the clearance of Plasmodium falciparum gametocytes. However, the use of this drug is limited by its toxicity. To circumvent this shortfall the search for additional drugs that can clear gametocytes is a research priority. The aim of this project was to ‘target’ P. falciparum gametocytes in order to progress the gametocyte drug discovery process. Two different approaches were used. The first was to define the gametocytocidal properties of tafenoquine (TQ) a new antimalarial with potential activity against gametocytes. The second was to investigate the potential of plasmepsin IX (PfPM IX) and X (PfPM X) as targets for the development of new anti-gametocyte drugs. TQ, an analogue of PQ, may have activity against P. falciparum gametocytes. However, its efficacy against gametocytes is poorly defined and complicated by the possibility that it may be mediated by metabolites. To further define the efficacy of TQ against gametocytes new ex vivo and in vivo methods were developed to study the activity of this drug and its metabolites against P. falciparum gametocytes. Data generated in these studies demonstrate that TQ is active against mature P. falciparum gametocytes in vitro (IC50 5 µM). However, activity occurs at concentrations that are unlikely to be achieved in vivo (Cmax range 0.9-2 µM; 400 mg administered daily for 3 days). While associated with their individual limitations, ex vivo and in vivo studies designed to incorporate the assessment of TQ metabolites, also suggested that this drug is likely to have limited activity against gametocytes in the field. A novel mouse model was developed to examine the in vivo activity of TQ against P. falciparum gametocytes. This model used immune-deficient mice to enable mature P. falciparum gametocytes to be maintained for sufficient time to assess drug efficacy. Further treatment to suppress the immune system of mice, including the administration of liposomal clodronate and individual splenectomies, were also required to limit parasite clearance so drug activity could be assessed. PQ was active in this model. Currently available data suggest that HIV protease inhibitors (HIV PIs), used to treat HIV infection, are also active against multiple stages of P. falciparum parasite development and that these drugs may target PfPM IX and/or PfPM X. To examine if PfPM IX or PfPM X are good anti-gametocyte drug targets the expression and location of these enzymes was investigated in gametocytes. Examination of transcription by RT-PCR demonstrated that PfPM IX and PfPM X are transcribed by gametocytes. However, examination of protein expression by Western blot and immunofluorescence assays revealed that PfPM X may not be translated in mature gametocytes. This indicates that PfPM X is transcribed, but translationally repressed perhaps to ensure rapid production of protein later in the lifecycle. Genes thought to be important in the process of sporogony have been shown to undergo this process. In contrast to PfPM X, PfPM IX is transcribed and translated in stage V gametocytes. These data suggest that PfPM IX is more likely to be the target of HIV PIs in gametocytes and that this enzyme, along with the other poorly characterized gametocyte specific PfPMs VI-VIII, warrant further investigation as anti-gametocyte drug targets. HIV PIs with activity against asexual stages not yet assessed for anti-gametocyte activity, nomilin, limonin and BR124, were also screened for gametocytocidal action, but were not active at 20 µM. This current body of research has progressed our understanding of TQ and its potential as an anti-gametocyte agent and in doing so has facilitated the development of the first in vivo mouse model able to assess the activity of drugs against P. falciparum gametocytes. It has also demonstrated that PfPM IX is expressed in gametocytes and warrants further investigation as a drug target in these parasites. The current study also uncovered that PfPM X is not translated to a detectable degree in gametocytes and as a result is unlikely to be the target of HIV PIs in these parasites and should not be considered an anti-gametocyte drug target.