Malaria is a devastating disease, responsible for approximately one million deaths each year and socio-economic disparities worldwide. The emergence of multiple drug-resistant Plasmodium strains to current artemisinin-combination therapies is raising major concerns for the treatment of malaria and urging for the development of new antimalarial drugs. Whereas existing therapies exclusively target the blood stage of infection, only limited efforts have been made to date to specifically target the liver stage of th Plasmodium life cycle. Plasmodium parasites go through an obligatory developmental phase in the liver, which is asymptomatic. However, the molecular requirements for host-parasite interactions that contribute to the liver stage are poorly understood. Therefore, investigation of the host cell determinants in the liver stage will provide a better understanding of molecular processes involved in Plasmodium pathogenesis. We have employed an unbiased functional RNA interference approach to identify new host cell factors that are critical to Plasmodium infection of liver cells. Our screen reveals ~1% of human genes (from a 7,000 gene library) whose siRNA knockdown significantly reduces parasite load in hepatocytes. Gene ontology for these genes revealed a broad distribution of biological functions including biological regulation, metabolic processes, cell proliferation, and cell communication. Further investigation reveals three genes among these screening hits, i.e. CACNA1D, GPRC6A and REEP5, exhibiting the strongest inhibitory phenotype without any cytotoxicity. We hypothesize that Plasmodium parasites manipulate these genes to promote liver stage development. Therefore, we propose an interdisciplinary approach combining functional genomic and pharmacological strategies, and immunofluorescence microscopy to investigate host-Plasmodium interactions in liver cells. Specifically, I will 1) perform functional rescue experiments to validate the screenin hits as essential during liver stage infection. Moreover, I will 2) characterize the modulation of CACNA1D, GPRC6A and REEP5, and 3) investigate their signaling mechanisms during Plasmodium infection of liver cells. This project will expand our understanding of fundamental host-parasite interactions occurring during the liver stage of malaria.