Antimalarial drugs that effectively kill the transmission stage of the malaria parasite lifecycle, the gametocyte, are recognized as key tools required for the global elimination of malaria. Currently only one drug, primaquine, is clinically available for the clearance of Plasmodium falciparum gametocyte stages, however the use of this drug is limited by toxicity. Therefore, the search for new antimalarials that can clear gametocytes is an important priority in malaria research. Unfortunately methods that enable the identification of potential anti-gametocyte agents in in vivo animal studies are limited. Animal studies are important as they enable the activity of metabolites to be assessed. In vivo methods for examining the activity of compounds against gametocytes rely on mouse models and murine Plasmodium species. While these models are useful, their relevance to human disease, particularly falciparum malaria is questionable due to significant differences in gametocyte development. To improve the current position we have developed a mouse model that enables P. falciparum gametocytes to be studied in vivo. Maintenance of the gametocytes within mice requires manipulation of the mouse immune system. Infection is established in SCID mice (deficient in B and T lymphocytes) that are administered liposomal clodronate to deplete macrophages. Clearance of parasites is also limited by removing the host’s spleen and overwhelming the immune system with human erythrocytes prior to infection. Pure gametocyte cultures are FITC stained before injection and the kinetics of gametocyte clearance assessed by fluorescence activated cell sorting. Humanized mouse models provide a novel and accessible means of anti-gametocyte antimalarial assessment and enable the important step of in vivo analysis prior to human trials in the drug development pipeline. The steps involved in the development of the model and data from the validation of the model using currently available antimalarials will be presented.